Adhesive compositions and related methods

ABSTRACT

Adhesive compositions and patches, and associated systems, kits, and methods, are generally described. Certain of the adhesive compositions and patches can be used to treat tissues (e.g., in hemostatic or other tissue treatment applications), according to certain embodiments.

TECHNICAL FIELD

Adhesive compositions and related methods are generally described.

BACKGROUND

Hemostatic agents and tissue sealants are routinely used to preventexcess blood loss and to reconstruct tissue during surgical repair. Forexample, fibrin glue is commonly used to impart topical hemostasis,provide sealant properties that are suitable in certain clinicalapplications, and promote tissue approximation. However, in general,commercially available tissue sealants do not perform well in wet or“bleeding” applications. Current commercially available tissue sealantsand hemostatic agents are generally too slow, too cumbersome, lackoptimum adhesive properties, and/or lack the tensile strength requiredfor suturing and preventing arterial blood loss. In addition, manycommercially available sealants do not have the mechanical strength toaddress many clinical wound closure demands.

Accordingly, improved adhesive compositions and patches are desirable.

SUMMARY

Disclosed herein are adhesive compositions and patches, includingrelated methods. Certain of the adhesive compositions and patches can beused to treat biological tissues (e.g., in hemostatic or other tissuetreatment applications), according to certain embodiments. The subjectmatter of the present invention involves, in some cases, interrelatedproducts, alternative solutions to a particular problem, and/or aplurality of different uses of one or more systems and/or articles.

In one set of embodiments, methods are provided. In one embodiment, amethod of forming an adhesive matrix comprises establishing a mixturecomprising a non-aqueous liquid, a first polyacrylic acid crosslinkedwith pentaerythritol and/or allyl sucrose, and a second polyacrylic acidcrosslinked with divinyl glycol on a substrate, applying a non-aqueouspolar solvent to the mixture on the substrate, and allowing at least aportion of the non-aqueous liquid and the non-aqueous polar solvent toevaporate to produce the adhesive matrix. In such embodiments, theamount of water in the mixture is less than or equal to about 2 wt. %,the non-aqueous solvent is made up of at least about 90 wt. % ofethanol, and after the evaporation, the sum of the amount of thenon-aqueous liquid and the non-aqueous polar solvent in the adhesivematrix is between about 0.001 wt % and about 3 wt %.

In one set of embodiments, tissue adhesive composites are provided. Inone embodiment, a tissue adhesive composite comprises a tissue adhesivefilm positioned on at least a portion of a substrate, wherein the tissueadhesive film comprises a first polyacrylic acid crosslinked withpentaerythritol and/or allyl sucrose, a second polyacrylic acidcrosslinked with divinyl glycol, and a liquid comprising ethanol. Insuch embodiments, greater than or equal to about 90 wt % of the tissueadhesive film is made up of polyacrylic acid, and less than about 8 wt %of the tissue adhesive film is made up of the liquid.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIG. 1A is a schematic of an adhesive composition, according to certainembodiments;

FIG. 1B is a schematic of an adhesive composition, according to certainembodiments;

FIG. 2 is, according to certain embodiments, graphs of burst pressurefor adhesive compositions comprising various polyacrylic acids;

FIG. 3A is a graph of burst pressure for adhesive compositionsmanufactured using various methods, according to some embodiments;

FIG. 3B is a graph of burst pressure for adhesive compositionsmanufactured using various methods, according to some embodiments;

FIG. 4 is a graph of maximum load for adhesive compositions manufacturedusing various methods, according to one set of embodiments; and

FIG. 5 is a graph of maximum load for adhesive compositions with variousweight percentages of polyacrylic acid, according to one set ofembodiments.

DETAILED DESCRIPTION

Adhesive compositions that can be used to treat biological tissues(e.g., in hemostatic or other tissue treatment applications) and relatedmethods are provided. In some embodiments, the adhesive composition mayinclude an adhesive matrix comprising a relatively high amount ofpolyacrylic acid and low amount of liquid. For instance, the adhesivecomposition may contain at least about 50 wt. % (e.g., at least about 75wt. %) polyacrylic acid, but less than about 8 wt. % of liquid (e.g., 5wt. %). In certain embodiments, the adhesive matrix comprises two ormore different polyacrylic acids that can interact with one another(e.g., via hydrogen bonding) to form a strong, cohesive, andbiocompatible adhesive matrix, when mixed together and applied asdescribed herein. The resulting adhesive matrix may, according tocertain although not necessarily all embodiments, have improvedadherence (e.g., to biological tissue) and/or strength compared tosubstantially the same composition formed via a different method and/orcompared to the individual polyacrylic acids alone. Methods of formingsuch an adhesive matrix may employ a polyacrylic acid dispersion andliquid displacement process while utilizing a relatively low amount ofor no water.

Adhesive compositions are often used in biological applications to join,seal, and/or otherwise adhere material (e.g., tissue). While numerousadhesive compositions exist, many conventional adhesive compositionsface a trade-off between beneficial properties (e.g., adhesive strength,tensile strength, burst strength) and biocompatibility. That is, one ormore properties (and accordingly, the utility associated with suchproperties) of certain conventional compositions are often limited dueto the constraints imposed by the requirement for biocompatibility.There remains a need for high adhesive and mechanical strength,biocompatible adhesive compositions.

It has been discovered, according to certain although not necessarilyall embodiments, that when certain polyacrylic acids (and mixtures) aresubjected to processes involving dispersion in certain non-aqueousliquids, subsequent displacement of the non-aqueous liquids with certainnon-aqueous solvents, and subsequent evaporation of the liquid andsolvent, the resulting adhesive matrix, surprisingly, has superioradhesive and mechanical properties compared to adhesive matrices havingsimilar or substantially the same composition formed via a differentmethod (e.g., a single solvent method, methods in which water-basedliquids are used) and compared to certain conventional biologicaladhesive compositions (e.g., powders, including certain polyacrylic acidpowders). The resulting adhesive matrix may also have, according tocertain embodiments, a relatively low liquid (e.g., residual solvent)content without the need for additional, time consuming, and/orexpensive solvent removal (e.g., washing) processes.

In one set of embodiments, methods are provided. In some embodiments, amethod for forming an adhesive composition comprises a dispersion stepand a liquid displacement step (which may be performed subsequent to thedispersion step). The dispersion step may include establishing (e.g.,distributing, applying) a mixture comprising at least one polyacrylicacid and a non-aqueous liquid on a substrate. In some cases, thepolyacrylic acid(s) is relatively evenly dispersed (e.g., viadissolution or suspension) within the non-aqueous liquid, such that arelatively homogenous mixture is formed. In some such embodiments,application of the mixture to at least a portion (e.g., substantiallyall, entire) of at least one surface of the substrate may serve torelatively evenly distribute the polyacrylic acid(s) on the substrate.

As used herein, the term “non-aqueous liquid” refers to a liquid that isnot water.

In some embodiments, the mixture may include a relatively low weightpercentage of water. For instance, in some embodiments, the mixturecontains less than or equal to about 10 wt. %, less than or equal toabout 8 wt. %, less than or equal to about 6 wt. %, less than or equalto about 5 wt. %, less than or equal to about 2 wt. %, less than orequal to about 1 wt. %, less than or equal to about 0.5 wt. %, less thanor equal to about 0.1 wt. %, less than or equal to about 0.05 wt. %, orless than or equal to about 0.01 wt. %. In some instances, the mixturemay contain 0 wt. % water. It has been discovered that, in someembodiments, the presence of substantial amounts of water in the mixtureapplied to the substrate may negatively affect the adhesive and/ormechanical properties of the resulting adhesive composition.

In some embodiments, the mixture may include a relatively high weightpercentage of the non-aqueous liquid(s). For instance, in someembodiments, the weight percentage of the non-aqueous liquid in themixture may be greater than or equal to about 50%, greater than or equalto about 55 wt. %, greater than or equal to about 75 wt. %, greater thanor equal to about 80 wt. %, greater than or equal to about 85 wt. %,greater than or equal to about 90 wt. %, greater than or equal to about95 wt. %, greater than or equal to about 96 wt. %, greater than or equalto about 97 wt. %, greater than or equal to about 98 wt. %, greater thanor equal to about 98.5 wt. %, greater than or equal to about 99 wt. %,or greater than or equal to about 99.5 wt. %. In some instances, theweight percentage may be less than or equal to about 100 wt. %, lessthan or equal to about 99.5 wt. %, less than or equal to about 99 wt. %,less than or equal to about 98.5 wt. %, less than or equal to about 98wt. %, less than or equal to about 97 wt. %, less than or equal to about96 wt. %, less than or equal to about 95 wt. %, less than or equal toabout 90 wt. %, less than or equal to about 85 wt. %, less than or equalto about 80 wt. %, less than or equal to about 75 wt. %, less than orequal to about 70 wt. %, less than or equal to about 65 wt. %, or lessthan or equal to about 60 wt. %. Combinations of the above referencedranges are also possible (e.g., greater than or equal to 50 wt. % andless than or equal to about 100 wt. %, greater than or equal to 75 wt. %and less than or equal to about 100 wt. %). According to certainembodiments, the mixture may comprise a combination of two or morenon-aqueous liquids. When two or more non-aqueous liquids are present inthe mixture, according to some embodiments, the total amount of allnon-aqueous liquids in the mixture can be within any of the rangesoutlined above.

In some embodiments, the mass ratio of the total mass of polyacrylicacid(s) to the total mass of non-aqueous liquid(s) within the mixture isfrom about 1:10 to about 1:1. In some embodiments, the mass ratio of thetotal mass of polyacrylic acid(s) to the total mass of non-aqueousliquid(s) within the mixture is greater than or equal to about 1:10,greater than or equal to about 1:9, greater than or equal to about 1:8,greater than or equal to about an 1:6, greater than or equal to about1:5, greater than or equal to about 1:4, greater than or equal to about1:3, greater than or equal to about 1:2, greater than or equal to about1:1.5, or greater than or equal to about 1:1.2. In some instances, themass ratio of the total mass of polyacrylic acid(s) to the total mass ofnon-aqueous liquid(s) within the mixture is less than or equal to about1:1, less than or equal to about 1:1.2, less than or equal to about1:1.5, less than or equal to about 1:2, less than or equal to about 1:3,less than or equal to about 1:4, less than or equal to about 1:5, lessthan or equal to about 1:6 less than or equal to about 1:8, or less thanor equal to about 1:10. Combinations of the above-referenced ranges arealso possible (e.g., greater than or equal to about 1:10 and less thanor equal to about 1:1).

In general, the mixture comprising the polyacrylic acid(s) and thenon-aqueous liquid(s) may be established (e.g., applied) on thesubstrate using a variety of suitable techniques. For instance, in someembodiments, the mixture may be applied to the substrate via casting,spin coating, dip coating, or spray coating. In certain embodiments, themixture may form a film on the surface of the substrate. In certainembodiments, establishing (e.g., applying) the mixture of polyacrylicacid(s) and non-aqueous liquid(s) comprises first mixing the polyacrylicacid(s) and the non-aqueous liquid(s), and subsequently applying themixture to the substrate. In some embodiments, applying the mixture ofpolyacrylic acid(s) and non-aqueous liquid(s) comprises separatelyapplying the polyacrylic acid(s) and the non-aqueous liquid(s) to thesubstrate, and mixing the components together to form the mixture on thesubstrate.

According to certain embodiments, removal of large amounts of thenon-aqueous liquid prior to application of the non-aqueous polar solventis not desirable, as such high rates of removal can lead to coagulationof the polyacrylic acid, which can result in the formation of anadhesive matrix that is not mechanically robust. However, in some cases,after application of the mixture to the substrate, a portion of thenon-aqueous liquid may be removed (e.g., via evaporation) prior toaddition of another liquid (e.g., the non-aqueous polar solventdescribed below). In some embodiments, up to about 10 wt. %, up to about20 wt. %, up to about 30 wt. %, up to about 40 wt. %, up to about 50 wt.%, up to about 60 wt. %, up to about 70 wt. %, or more of thenon-aqueous liquid may be removed prior to addition of another liquid(e.g., prior to the addition of the non-aqueous polar solvent). In somecases, the mass ratio of the total mass of non-aqueous liquid(s) to thetotal mass of polyacrylic acid(s) is at a relatively high level when asecond liquid (e.g., the non-aqueous polar solvent discussed below) isapplied to the mixture. For example, in some embodiments, the mass ratioof the total mass of non-aqueous liquid(s) to the total mass ofpolyacrylic acid(s) is at least about 1:1 (e.g., at least about 5:1)when a second liquid (e.g., the non-aqueous polar solvent discussedbelow) is applied to the mixture.

In some embodiments, the time between application of the mixture to atleast a portion of a substrate and a subsequent liquid application step(e.g., applying a non-aqueous polar solvent, as described below) may berelatively short. For instance, in some embodiments, the time betweenapplication of the mixture to the substrate and a subsequent method step(e.g., applying a non-aqueous polar solvent, as described below) may beless than or equal to about 20 minutes, less than or equal to about 18minutes, less than or equal to about 16 minutes, less than or equal toabout 15 minutes, less than or equal to about 14 minutes, less than orequal to about 13 minutes, or less than or equal to about 12 minutes andgreater than or equal to about 5 minutes (and/or, in certainembodiments, greater than or equal to about 8 minutes, or greater thanor equal to about 10 minutes). In some embodiments, a subsequent stepmay occur when the concentration of a component in the mixture changesby at least about 5% (e.g., at least about 50%) and/or the temperatureof the mixture increases by at least about 5° C. (e.g., at least about20° C.).

Non-limiting examples of non-aqueous liquids that may be mixed with thepolyacrylic acid(s) include ethyl acetate, tetrahydrofuran, diethylether, dioxane, pyridine, triethylamine, benzene, p-cresol, toluene,xylene, diethyl ether, glycol, diethyl ether, petroleum ether, hexane,cyclohexane, pentane, methylene chloride, chloroform, carbontetrachloride, dioxane, tetrahydrofuran (THF), dimethyl sulfoxide,dimethylformamide, hexamethyl-phosphoric triamide, pyridine,triethylamine, picoline, and mixtures thereof. In some embodiments, thenon-aqueous liquid may comprise ethyl acetate.

As noted above, in some embodiments, the step of establishing (e.g.,applying) a mixture comprising polyacrylic acid(s) and non-aqueousliquid(s) can be followed by a liquid displacement step. In someembodiments, the displacement step may include applying a non-aqueouspolar solvent (e.g., ethanol) to the mixture on the substrate. In somecases, the non-aqueous polar solvent may serve to displace at least aportion of the non-aqueous liquid and/or disrupt the association betweenat least a portion of the polyacrylic acid molecules and the non-aqueousliquid molecules and/or promote interaction between certain matrixcomponents (e.g., one or more polyacrylic acids). In certainembodiments, the displacement step may facilitate the arrangement of thepolyacrylic acid(s) in the mixture and/or evaporation of the non-aqueousliquid and/or non-aqueous polar solvent. For instance, the non-aqueouspolar solvent may facilitate interaction between matrix component(s) inthe mixture. As another example, the non-aqueous polar solvent mayfacilitate hydrogen bonding between polyacrylic acid molecules in themixture. The hydrogen bonding may contribute to the formation of acohesive matrix, according to certain embodiments.

As used herein, the term “non-aqueous polar solvent” refers to a polarsolvent that is not water. In some embodiments, the non-aqueous polarsolvent solvates at least a portion of the polyacrylic acid molecules inthe mixture. In certain embodiments, the non-aqueous polar solvent is aliquid.

As used herein, the term “polar solvent” refers to a solvent having adielectric constant of greater than about 5. In some instances, thepolar solvent may have a dielectric constant greater than about 5 andless than or equal to about 300. The dielectric constant may be measuredat 20° C. using methods known in the art. Dielectric constants forsolvents can be found in, e.g., the CRC Handbook of Chemistry andPhysics. 96th ed. CRC Press: Boca Raton, Fla., 2015-2016.

A relatively low amount of water may be present in the mixture prior to,during, and/or after the addition of the non-aqueous polar solvent. Forinstance, in some embodiments, the amount of water present in themixture prior to, during, and/or after the addition of the non-aqueoussolvent may be less than or equal to about 10 wt. %, less than or equalto about 8 wt. %, less than or equal to about 6 wt. %, less than orequal to about 5 wt. %, less than or equal to about 2 wt. %, less thanor equal to about 1 wt. %, less than or equal to about 0.5 wt. %, lessthan or equal to about 0.1 wt. %, less than or equal to about 0.05 wt.%, or less than or equal to about 0.01 wt. % of the mixture. In someinstances, water may not be present in the mixture prior to, during,and/or after the addition of the non-aqueous polar solvent.

In some embodiments, the mass ratio of total amounts of non-aqueouspolar solvent(s) to total mass of the mixture to which it is applied maybe relatively low. For instance, in some embodiments, the mass ratios oftotal amounts of non-aqueous polar solvent(s) to total mass of themixture to which it is applied may be less than or equal to about 1:1,less than or equal to about 1:1.2, less than or equal to about 1:1.5,less than or equal to about 1:2, less than or equal to about 1:3, lessthan or equal to about 1:4, less than or equal to about 1:5, less thanor equal to about 1:6, less than or equal to about 1:8, or less than orequal to about 1:10. In some instances, the mass ratio of the total massof polyacrylic acid(s) to the total mass of non-aqueous liquid(s) withinthe mixture is greater than or equal to about 1:10, greater than orequal to about 1:9, greater than or equal to about 1:8, greater than orequal to about an 1:6, greater than or equal to about 1:5, greater thanor equal to about 1:4, greater than or equal to about 1:3, greater thanor equal to about 1:2, greater than or equal to about 1:1.5, or greaterthan or equal to about 1:1.2. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to about 1:10 andless than or equal to about 1:1).

In general, the non-aqueous polar solvent may be applied to the mixtureusing any suitable technique. For instance, in some embodiments, thenon-aqueous polar solvent may be applied to the mixture via spraycoating, misting, casting, spin coating, and/or dip coating. In someembodiments, the non-aqueous polar solvent may be applied to the mixturein a manner that allows a relatively large percentage of the exposedsurface of the mixture to be exposed to the non-aqueous polar solvent.For instance, the percent exposed surface area of mixture that isexposed to the non-aqueous polar solvent may be greater than or equal toabout 50%, greater than or equal to about 60%, greater than or equal toabout 70%, greater than or equal to about 80%, greater than or equal toabout 90%, greater than or equal to about 95%, greater than or equal toabout 96%, greater than or equal to about 97%, greater than or equal toabout 98%, or greater than or equal to about 99%.

In some embodiments, the time between application of the non-aqueouspolar solvent to the mixture and a subsequent method step (such asliquid removal, e.g., via drying), may be relatively short. Forinstance, in some embodiments, the time between application to thesubstrate and a subsequent method step may be less than or equal toabout 15 minutes, less than or equal to about 12 minutes, less than orequal to about 10 minutes, less than or equal to about 8 minutes, lessthan or equal to about 6 minutes, less than or equal to about 5 minutes,or less than or equal to about 4 minutes and greater than or equal toabout 1 minutes (e.g., greater than or equal to about 2 minutes). Insome embodiments, a subsequent step may occur when the concentration ofa component in the mixture changes by at least about 5% (e.g., at leastabout 50%) and/or the temperature of the mixture increases by at leastabout 5° C. (e.g., at least about 20° C.).

Non-limiting examples of non-aqueous polar solvents that may be appliedto the mixtures of polyacrylic acid(s) and non-aqueous liquid(s)described herein include but are not limited to polar aprotic solvents(e.g., dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate,acetone, dimethylformamide (DMF), acetonitrile, dimethyl sulfoxide(DMSO), and propylene carbonate) and polar protic solvents (e.g., formicacid, n-butanol, isopropanol, n-propanol, ethanol, methanol, aceticacid, nitromethane, sugar alcohols, non-ionic surfactants), and mixturesthereof. The non-aqueous polar solvent can comprise, according tocertain embodiments, an organic solvent. In certain embodiments, thenon-aqueous polar solvent comprises an alcohol. The non-aqueous polarsolvent comprises, in some embodiments, at least one of methanol,ethanol, and propanol (e.g., isopropanol). In certain, but notnecessarily all embodiments, it can be advantageous to use a non-aqueouspolar solvent comprising ethanol as the non-aqueous polar solvent. Insome embodiments, the non-aqueous polar solvent comprises ethanol andmethanol.

In some embodiments, certain additives may be applied to the mixture onthe substrate prior to, along with, and/or subsequent to the addition ofthe non-aqueous solvent. For example, glycerol may be applied to themixture on the substrate along with the non-aqueous polar solvent (e.g.,ethanol). Non-limiting examples of suitable additives include glycerol,polyethylene glycol, polysorbate, and sugar alcohols.

In some embodiments, the total weight percentage of additives in themixture (e.g., prior to, during, and/or after addition of thenon-aqueous polar solvent) may be relatively small. For instance, thetotal weight percentage of the additives in the mixture be less than orequal to about 10 wt. %, less than or equal to about 8 wt. %, less thanor equal to about 6 wt. %, less than or equal to about 5 wt. %, lessthan or equal to about 4 wt. %, less than or equal to about 3 wt. %,less than or equal to about 2 wt. %, less than or equal to about 1 wt.%, less than or equal to about 0.5 wt. %, or less than or equal to about0.1 wt. %. In some instances, the weight percentage may be greater thanor equal to about 0.01 wt. %, greater than or equal to about 0.05 wt. %,greater than or equal to about 0.1 wt. %, greater than or equal to about0.5 wt. %, greater than or equal to about 1 wt. %, greater than or equalto about 2 wt. %, greater than or equal to about 3 wt. %, greater thanor equal to about 4 wt. %, greater than or equal to about 5 wt. %,greater than or equal to about 6 wt. %, or greater than or equal toabout 8 wt. %. Combinations of the above referenced ranges are alsopossible (e.g., greater than or equal to 0.01 wt. % and less than orequal to about 10 wt. %)

In some embodiments, at least a portion of (and, in many instances, arelatively large percentage of) the non-aqueous liquid and/or thenon-aqueous polar solvent may be removed (e.g., via evaporation) toproduce the adhesive matrix. In some embodiments, after the removalstep, the amount of residual solvent (i.e., liquid remaining from priormethod steps) may be relatively low. For instance, according to certainembodiments, after at least a portion of the non-aqueous liquid and/orthe non-aqueous polar solvent have been removed, the sum of the amountof the non-aqueous liquid and the non-aqueous polar solvent in theadhesive matrix is less than or equal to about 8 wt. % (e.g., less thanor equal to about 5 wt. %, less than or equal to about 3 wt. %, lessthan or equal to about 1 wt. %, less than or equal to about 0.5 wt. %,or less than or equal to about 0.1 wt. %). Evaporation of thenon-aqueous liquid and/or the non-aqueous polar solvent may result inthe formation of an adhesive matrix, such as an adhesive film. Theadhesive matrix may have beneficial properties due in part to theinteraction between matrix components induced, in part, by dispersionand/or displacement processes described above. For example, in somecases, the adhesive matrix may have a cohesive structure. In some cases,the adhesive matrix may be self-supporting, and optionally flexibleand/or elastic. In some cases, the adhesive matrix may be cross-linked.

In general, any suitable liquid removal method may be used to remove thenon-aqueous liquid and/or non-aqueous polar solvent. For instance, theliquid may be removed by applying energy (e.g., thermal energy) toinduce evaporation. In some cases, the liquid may be removed viaevaporation without the substantial application of energy by a user.

As used herein, the term “residual solvent” refers to the amount ofliquid (e.g., non-aqueous liquid and non-aqueous polar solvent) used inthe fabrication of the adhesive matrix that remains in the adhesivematrix after the liquid removal step.

In some embodiments, the weight percentage of the sum of the non-aqueousliquid(s) and the non-aqueous polar solvent(s) in the adhesive matrixand/or composition after the liquid removal (e.g., evaporation) step maybe less than or equal to about 8 wt. %, less than or equal to about 5wt. %, less than or equal to about 4 wt. %, less than or equal to about3 wt. %, less than or equal to about 2 wt. %, less than or equal toabout 1 wt. %, less than or equal to about 0.5 wt. %, less than or equalto about 0.1 wt. %, less than or equal to about 0.05 wt. %, less than orequal to about 0.01 wt. %, less than or equal to about 0.005 wt. %, lessthan or equal to about 0.001 wt. %, or less than or equal to about0.0005 wt. %. In some instances, the weight percentage may be greaterthan or equal to about 0.0001 wt. %, greater than or equal to about0.0005 wt. %, greater than or equal to about 0.001 wt. %, greater thanor equal to about 0.005 wt. %, greater than or equal to about 0.01 wt.%, greater than or equal to about 0.05 wt. %, greater than or equal toabout 0.1 wt. %, or greater than or equal to about 0.5 wt. %.Combinations of the above referenced ranges are also possible (e.g.,greater than or equal to 0.001 wt. % and less than or equal to about 8wt. %, greater than or equal to 0.001 wt. % and less than or equal toabout 3 wt. %, greater than or equal to 0.0001 wt. % and less than orequal to about 1 wt. % greater than or equal to 0.0001 wt. % and lessthan or equal to about 0.1 wt. %). In embodiments in which more than onetype of liquid (e.g., non-aqueous polar solvent, no-aqueous liquid) ispresent in the adhesive matrix, each type of liquid (e.g., non-aqueouspolar solvent, non-aqueous liquid) may independently have a weightpercentage with respect to the adhesive matrix in one or more of theranges described above, provided that the total percentage is less thanor equal to about 5 wt. %.

In general, the method is performed with minimal use of water. Forinstance, in some embodiments, the amount of water in the mixture at anypoint during the method may be less than or equal to about 10 wt. %,less than or equal to about 8 wt. %, less than or equal to about 6 wt.%, less than or equal to about 5 wt. %, less than or equal to about 2wt. %, less than or equal to about 1 wt. %, less than or equal to about0.5 wt. %, less than or equal to about 0.1 wt. %, less than or equal toabout 0.05 wt. %, or less than or equal to about 0.01 wt. %.

It has been discovered that, according to certain, although notnecessarily all embodiments, the use of a mixture of a first polyacrylicacid cross-linked with pentaerythritol and/or allyl sucrose and a secondpolyacrylic acid cross-linked with divinyl glycol can lead to theproduction of adhesive matrices with enhanced adhesive and/or mechanicalproperties. In some such embodiments, the properties of the resultantadhesive matrix are further enhanced when low amounts of water are usedduring processing. Accordingly, in some embodiments, a method of formingthe adhesive matrix comprises applying a mixture comprising anon-aqueous liquid, a first polyacrylic acid cross-linked withpentaerythritol and/or allyl sucrose, and a second polyacrylic acidcross-linked with divinyl glycol to a substrate, wherein the amount ofwater in the mixture is less than or equal to about 2 wt. %. It has alsobeen discovered that the use of ethanol as a non-aqueous polar solventcan be particularly advantages, according to certain although notnecessarily all embodiments. According, in some embodiments, anon-aqueous polar solvent containing ethanol in an amount of at leastabout 90 wt. % may be applied to the mixture on the substrate and atleast a portion of the non-aqueous liquid and the non-aqueous polarsolvent may be allowed to evaporate to produce the adhesive matrix. Insome such embodiments, after the evaporation, the sum of the amount ofthe non-aqueous liquid and the non-aqueous polar solvent in the adhesivematrix is between about 0.001 wt. % and about 3 wt. % (or, in someembodiments, between about 0.001 wt. % and about 2 wt. %, or betweenabout 0.001 wt. % and about 1 wt. %).

Certain embodiments are related to adhesive matrices, which may beformed, in some cases, via certain of the methods described herein. Insome embodiments, at least about 50 wt. % of the adhesive matrix is madeup of at least one polyacrylic acid (e.g. a single polyacrylic acid, twopolyacrylic acids, or more polyacrylic acids) and less than about 8 wt.% (e.g., less than about 5 wt. %) of the adhesive matrix is made up ofliquid (e.g., water, a non-aqueous liquid, a non-aqueous polar solvent).In certain embodiments, the adhesive matrix may include at least 75 wt.% of at least one polyacrylic acid and less than about 8 wt. % (e.g.,less than about 5 wt. %, between about 0.001 wt. % and 1 wt. %) liquid.In one example, the adhesive matrix comprises greater than or equal toabout 90 wt. % of polyacrylic acid and less than about 5 wt. % of analcohol, such as ethanol. The polyacrylic acid may include, according tocertain embodiments, a first polyacrylic acid cross-linked withpentaerythritol and/or allyl sucrose (e.g., carbomer) and a secondpolyacrylic acid cross-linked with divinyl glycol (e.g., polycarbophil).In some embodiments, the adhesive matrices may also have a relativelyhigh adhesive strength (e.g., a lap shear adhesive strength of at leastabout 4 pound force) and/or a relatively high mechanical strength (e.g.,burst strength of at least about 100 mmHg gauge).

According to certain but not necessarily all embodiments, it may beadvantageous to use a first polyacrylic acid homopolymer cross-linkedwith pentaerythritol and/or allyl sucrose and a second polyacrylic acidhomopolymer cross-linked with divinyl glycol. In some such embodiments,the total amount of the first and second polyacrylic acids within theadhesive matrix can be greater than or equal to about 50%, greater thanor equal to about 55%, greater than or equal to about 75%, greater thanor equal to about 80%, greater than or equal to about 85%, greater thanor equal to about 90%, greater than or equal to about 95%, greater thanor equal to about 96%, greater than or equal to about 97%, greater thanor equal to about 98%, greater than or equal to about 98.5%, greaterthan or equal to about 99%, or greater than or equal to about 99.5%.

In some embodiments, the weight percentage of all polyacrylic acids(e.g., polycarbophil and carbomer) in the adhesive matrix and/orcomposition may be greater than or equal to about 50%, greater than orequal to about 55%, greater than or equal to about 75%, greater than orequal to about 80%, greater than or equal to about 85%, greater than orequal to about 90%, greater than or equal to about 95%, greater than orequal to about 96%, greater than or equal to about 97%, greater than orequal to about 98%, greater than or equal to about 98.5%, greater thanor equal to about 99%, or greater than or equal to about 99.5%. In someinstances, the weight percentage may be less than or equal to about100%, less than or equal to about 99.5%, less than or equal to about99%, less than or equal to about 98.5%, less than or equal to about 98%,less than or equal to about 97%, less than or equal to about 96%, lessthan or equal to about 95%, less than or equal to about 90%, less thanor equal to about 85%, less than or equal to about 80%, less than orequal to about 75%, less than or equal to about 70%, less than or equalto about 65%, or less than or equal to about 60%. Combinations of theabove referenced ranges are also possible (e.g., greater than or equalto 50% and less than or equal to about 100%, greater than or equal to75% and less than or equal to about 100%). One of ordinary skill of theart would be knowledgeable of methods to determine the weight percentageof polyacrylic acid. For example, the weight percentage of polyacrylicacid in an adhesive composition may be determined using high pressureliquid chromatography (HPLC).

In some embodiments, the adhesive matrix may contain a relatively lowpercentage of liquid. For instance, in some embodiments, the weightpercentage of all liquid in the adhesive composition may be less than orequal to about 8 wt. %, less than or equal to about 5 wt. %, less thanor equal to about 4 wt. %, less than or equal to about 3 wt. %, lessthan or equal to about 2 wt. %, less than or equal to about 1 wt. %,less than or equal to about 0.5 wt. %, less than or equal to about 0.1wt. %, less than or equal to about 0.05 wt. %, less than or equal toabout 0.01 wt. %, less than or equal to about 0.005 wt. %, less than orequal to about 0.001 wt. %, or less than or equal to about 0.0005 wt. %.In some instances, the weight percentage may be greater than or equal toabout 0.0001 wt. %, greater than or equal to about 0.0005 wt. %, greaterthan or equal to about 0.001 wt. %, greater than or equal to about 0.005wt. %, greater than or equal to about 0.01 wt. %, greater than or equalto about 0.05 wt. %, greater than or equal to about 0.1 wt. %, greaterthan or equal to about 0.5 wt. %, greater than or equal to about 1 wt.%, greater than or equal to about 2 wt. %, greater than or equal toabout 3 wt. %, or greater than or equal to about 4 wt. %. Combinationsof the above referenced ranges are also possible (e.g., greater than orequal to 0.0001 wt. % and less than or equal to about 5 wt. %, greaterthan or equal to 0.0001 wt. % and less than or equal to about 1 wt. %greater than or equal to 0.0001 wt. % and less than or equal to about0.1 wt. %). In embodiments in which more than one type of liquid (e.g.,ethanol) is present in the adhesive matrix, each type of liquid (e.g.,non-aqueous polar solvent, non-aqueous liquid) may independently have aweight percentage with respect to the adhesive matrix in one or more ofthe ranges described above, provided that, for embodiments in which thetotal percentage of liquid falls within the above-described ranges, thetotal percentage is less than or equal to about 8 wt. % (e.g., less thanor equal to about 5 wt. %). The weight percentage may be determined asusing gas chromatography.

In some embodiments, in the adhesive matrix, the ratio of the total massof polyacrylic acid(s) (e.g., the first and second polyacrylic acids,and/or other polyacrylic acids) to the total mass of liquid(s) (e.g.,the residual non-aqueous liquid and/or non-aqueous polar solvent, and/orother liquids) is from about 10,000:1 to about 19:1. In someembodiments, in the adhesive matrix, the ratio of the total mass of thepolyacrylic acid(s) to the total mass of the liquid(s) is equal to orgreater than 19:1, equal to or greater than 25:1, equal to or greaterthan 50:1, equal to or greater than 75:1, equal to or greater than100:1, equal to or greater than 150:1, equal to or greater than 200:1,equal to or greater than 250:1, equal to or greater than 500:1, equal toor greater than 750:1, equal to or greater than 1,000:1, equal to orgreater than 2,500:1, equal to or greater than 5,000:1, or equal to orgreater than 7,500:1. In some instances, in the adhesive matrix, theratio of the total mass of the polyacrylic acid(s) to the total mass ofthe liquid(s) is less than or equal to about 10,000:1, less than orequal to about 7,500:1, less than or equal to about 5,000:1, less thanor equal to about 2,500:1, less than or equal to about 1,000:1, lessthan or equal to about 750:1, less than or equal to about 500:1, lessthan or equal to about 250:1, less than or equal to about 150:1, lessthan or equal to about 100:1, less than or equal to about 75:1, or lessthan or equal to about 50:1. Combinations of the above referenced rangesare also possible (e.g., greater than or equal to 19:1 and less than orequal to about 10,000:1, greater than or equal to 19:1 and less than orequal to about 1,000:1).

In some embodiments, the adhesive composition and/or matrix may notcontain water. In other embodiments, the adhesive composition and/ormatrix may contain a relatively low percentage of water. For instance,in some embodiments, the weight percentage of water in the adhesivecomposition may less than or equal to about 5%, less than or equal toabout 3%, less than or equal to about 1%, less than or equal to about0.5%, less than or equal to about 0.1%, less than or equal to about0.05%, less than or equal to about 0.01%, less than or equal to about0.005%, less than or equal to about 0.001%, or less than or equal toabout 0.0005%. In some instances, the weight percentage of water in theadhesive composition may be greater than or equal to about 0.0001%,greater than or equal to about 0.0005%, greater than or equal to about0.001, greater than or equal to about 0.005%, greater than or equal toabout 0.01%, greater than or equal to about 0.05%, greater than or equalto about 0.1%, greater than or equal to about 0.5%, or greater than orequal to about 1%. Combinations of the above referenced ranges are alsopossible (e.g., greater than or equal to 0.0001 wt. % and less than orequal to about 5 wt. %, greater than or equal to 0.0001 wt. % and lessthan or equal to about 1% greater than or equal to 0.0001 wt. % and lessthan or equal to about 0.1 wt. %).

In some embodiments, adhesive matrices produced via the inventivemethods disclosed may have superior adhesive and mechanical propertiesto many conventional tissue adhesives formed from similar materialsusing conventional techniques. For instance, in some embodiments, theadhesive matrix may have a relatively high burst strength. In someembodiments, the adhesive matrix may have a burst strength of greaterthan or equal to about 100 mmHg (gauge), greater than or equal to about150 mmHg (gauge), greater than or equal to about 200 mmHg (gauge),greater than or equal to about 250 mmHg (gauge), greater than or equalto about 300 mmHg (gauge), greater than or equal to about 350 mmHg(gauge), greater than or equal to about 400 mmHg (gauge), greater thanor equal to about 450 mmHg (gauge), or greater than or equal to about500 mmHg (gauge). In some instances, the burst strength may be less thanor equal to about 600 mmHg (gauge), less than or equal to about 550 mmHg(gauge), less than or equal to about 500 mmHg (gauge), less than orequal to about 450 mmHg (gauge), less than or equal to about 400 mmHg(gauge), less than or equal to about 350 mmHg (gauge), less than orequal to about 300 mmHg (gauge), less than or equal to about 250 mmHg(gauge), or less than or equal to about 200 mmHg (gauge). Combinationsof the above-referenced ranges are also possible (e.g., greater than orequal to about 100 mmHg (gauge) and less than or equal to about 600 mmHg(gauge), greater than or equal to about 150 mmHg (gauge) and less thanor equal to about 600 mmHg (gauge)). Other values of burst strength arealso possible. The burst strength may be determined according to thestandard ASTM F2392-04.

In some embodiments, the adhesive matrix may be a self-supportingmatrix. A matrix is generally considered to be self-supporting when thematrix does not dissociate into multiple pieces when suspended from oneend under the force of gravity. A cohesive film that can be handledwithout breaking into multiple pieces under the force of gravity is anexample of a material that is self-supporting. A layer of particulatepowder that cannot be handled without dissociating into individuatedparticles is an example of a material that is not self-supporting.

According to certain embodiments, the adhesive matrix may be flexible. Aflexible material is a material that can be elongated from anun-stressed state such that the length of at least one dimension of thematerial is increased to at least about 105% of the length of theun-stressed dimension without fracturing. According to certainembodiments, the adhesive matrix can be elongated from an un-stressedstate such that the length of at least one dimension of the adhesivematrix is increased to at least about 110%, at least about 125%, atleast about 150%, or at least about 200% of the length of theun-stressed dimension without fracturing.

In some embodiments, the adhesive matrix may be elastic. An elasticmaterial is a material that is capable of returning substantially to itsoriginal shape spontaneously after distortion (e.g., contraction ordilatation) from its original shape. In certain embodiments, at leastone dimension of the adhesive matrix exhibits substantially reversibledistortion when the dimension is compressed from its initial(un-stressed) length to a length that is less than about 95% of itsinitial length (or, in some embodiments, less than about 75%, less than60%, or less than 50% of its initial length). In some embodiments, atleast one dimension of the adhesive matrix exhibits substantiallyreversible distortion when the dimension is elongated from its initial(un-stressed) length to a length that is at least about 105% of itsinitial length (or, in some embodiments, at least about 110%, at leastabout 125%, at least about 150%, or at least about 200% of its initiallength). An article exhibits “substantially reversible distortion” when,after a dimension of the article has been deformed, the dimension of thearticle spontaneously returns to a length that is within 10% (or within5%, or within 2%) of its original length.

In certain embodiments, the adhesive matrix is continuous. In some suchcases, the coefficient of variation in the thickness of the adhesivematrix across at least a portion (e.g., across at least 90%, across atleast 95%, or across substantially 100%) of its surface is less than orequal to about 20% (e.g., less than or equal to about 20%, less than orequal to about 15%, less than or equal to about 10%, less than or equalto about 5%). In some embodiments, the adhesive matrix is not a powder.According to certain embodiments, less than 10 wt. %, less than 5 wt. %,or less than 1 wt. % of the adhesive matrix is made up of particulatematter having an average largest cross-sectional dimension of less thanor equal to about 100 nm.

In some embodiments, the adhesive matrix may have a lap shear adhesivestrength of greater than or equal to about 1.5 pound force, greater thanor equal to about 2 pound force, greater than or equal to about 2.5pound force, greater than or equal to about 3 pound force, greater thanor equal to about 3.5 pound force, greater than or equal to about 4pound force, greater than or equal to about 4.5 pound force, greaterthan or equal to about 5 pound force, greater than or equal to about 5.5pound force, greater than or equal to about 6 pound force, or greaterthan or equal to about 8 pound force. In some instances, the lap shearadhesive strength may be less than or equal to about 10 pound force,less than or equal to about 8 pound force, less than or equal to about7.5 pound force, less than or equal to about 7 pound force, less than orequal to about 6.5 pound force, less than or equal to about 6 poundforce, less than or equal to about 5.5 pound force, less than or equalto about 5 pound force, less than or equal to about 4.5 pound force,less than or equal to about 4 pound force, less than or equal to about3.5 pound force, less than or equal to about 3 pound force, or less thanor equal to about 2 pound force. Combinations of the above-referencedranges are also possible (e.g., greater than or equal to about 2 poundforce and less than or equal to about 10 pound force, greater than orequal to about 4 pound force and less than or equal to about 10 poundforce). Other values of burst strength are also possible. The lap shearadhesive strength may be determined according to the standard ASTMF2255-05 on a glass substrate instead of tissue.

Without being bound by theory, it is believed that the beneficialadhesive and mechanical strength of the adhesive matrix, describedherein, is due in part to the interactions between matrix componentsthat are allowed and/or induced to occur during formation of the matrix.It is believed that certain matrix components, such a differentpolyacrylic acids may physically entangled or form chemical bonds duringcertain portion of the method, as described in more detail below. Forinstance, in some embodiments, one or more matrix components (e.g.,polyacrylic acid) may associate with itself or another component via achemical interaction, such as a non-covalent bond or covalent bond. Insome cases, the bond is a non-covalent bond such as a hydrogen bond,ionic bond, dative bond, and/or a Van der Waals interaction. Forexample, one or more matrix components may include at least one hydrogenatom capable of interacting with a pair of electrons on a hydrogen-bondacceptor of a binding partner to form the hydrogen bond. In someembodiments, a molecule and/or a binding partner may include anelectron-rich or electron-poor moiety, such that it may form anelectrostatic interaction with another of a binding partner and/ormolecule, respectively. One or more of the matrix components (e.g.,polyacrylic acid) may comprise functional groups capable of forming suchbonds.

In general, any suitable polyacrylic acid may be used to form theadhesive matrix. In some embodiments, the polyacrylic acid(s) may beselected based on the intended use of the agent. For instance, in someembodiments, the polyacrylic acid(s) may be selected based on itscompatibility with pharmaceutical applications and other consumerproducts (e.g., cosmetics, food).

As used herein, the term “polyacrylic acid” refers to a polymer moleculewith or without cross-links comprising at least about 100 optionallysubstituted acrylic acid and/or acrylate repeat units, wherein thedegree of substitution of the acid or acrylate moiety is less than orequal to about 2 (e.g., less than or equal to about 0.8). In certainembodiments, the degree of substitution of the acid or acrylate moietyis less than or equal to about 2, less than or equal to about 1.8, lessthan or equal to about 1.5, less than or equal to about 1.2, less thanor equal to about 1, less than or equal to about 0.8, less than or equalto about 0.6, less than or equal to about 0.5, less than or equal toabout 0.4, less than or equal to about 0.3, or less than or equal toabout 0.2. In some embodiments, at least a portion of carboxylic acidmoieties in the polyacrylic acid may be optionally substituted. In suchcases, the degree of substitution of the carboxylic acid moieties in thepolyacrylic acid may be as described above. In certain embodiments, atleast a portion of the carboxylic acid moieties may be substituted witha cross-linking agent (e.g., allyl sucrose, divinyl glycol,pentaerythritol). In some embodiments, polymer molecules are generallyextended molecular structures comprising backbones which optionallycontain pendant side groups, wherein the term backbone is given itsordinary meaning as used in the art, e.g., a linear chain of atomswithin the polymer molecule by which other chains may be regarded asbeing pendant. Typically, but not always, the backbone is the longestchain of atoms within the polymer. Polymers may be linear or branched.In some embodiments, the polyacrylic acid(s) may be a co-polymer, forexample, a block, alternating, or random co-polymer. In other instances,the polyacrylic acid(s) are homopolymers. In certain embodiments inwhich the polyacrylic acid is a co-polymer, the mole fraction of acrylicacid and/or acrylate repeat unit in the co-polymer may be greater thanor equal to about 0.5, greater than or equal to about 0.6, greater thanor equal to about 0.7, greater than or equal to about 0.8, or greaterthan or equal to about 0.9 and less than or equal to about 1.0 (e.g.,less than or equal to about 0.9, less than or equal to about 0.8)

It should be understood that, when determining the mass and/or a weightpercentage of one or more “polyacrylic acids” within a particularcomponent (e.g., an adhesive matrix) the weight of the “polyacrylicacid” should include the weight of the entire polymer, includingcontributions from both the polyacrylic acid backbone any covalentlyattached moieties. For instance, the mass of covalently cross-linkedpolyacrylic acid includes the polyacrylic acid and the covalentlyattached cross-linking agent(s). As another example, the entire mass ofa co-polymer comprising polyacrylic acid would be included.

In some embodiments, the polyacrylic acid(s) may be cross-linked, forexample through covalent bonds, ionic bonds, hydrophobic bonds, and/ormetal binding. In some embodiments, the polyacrylic acid may becovalently cross-linked. In general, any suitable cross-linking methodmay be used. For instance, charged polyacrylic acid may be ionicallycross-linked to form a polymer matrix. Those of ordinary skill in theart would be knowledgeable of suitable cross-linking methods. In certainbut not necessarily all embodiments, the polyacrylic acid may include afirst polyacrylic acid cross-linked with pentaerythritol (e.g.,carbomer) and a second polyacrylic acid cross-linked with divinyl glycol(e.g., polycarbophil).

In some embodiments, the polyacrylic acid(s) may be biodegradable. Inother embodiments, the polyacrylic acid(s) may be non-degradable. Inembodiments where the adhesive matrices are to be comprised in acomposition for administration to a subject, the polyacrylic acid(s) maybe non-toxic and bioabsorbable.

Commercially available polyacrylic acids specifically contemplated foruse herein include, but are not limited to:

Carbopol® homopolymers which comprise acrylic acid cross-linked withallyl sucrose or allyl pentaerythritol (e.g., Carbopol®71G, 971P NF,974P NF, 980 NF, 981 NF, 5984 EP, 934 NF, 934P NF, 940 NF, 941 NF);

Carbopol® copolymers which comprise acrylic acid and C₁₀₋₃₀ alkylacrylate cross-linked with allyl pentaerythritol (e.g., Carbopol®1342NF);

Carbopol® interpolymers which comprise acrylic acid and/or C₁₀₋₃₀alkylacrylate, and a block co-polymer of polyethylene glycol and a long chainalkyl acid ester, cross-linked with allyl sucrose or allylpentaerythritol (e.g., Carbopol® ETD2020 NF, Ultrez 10 NF);

a polycarbophil polymer, such as Noveon® AA-1 Polycarbophil, whichcomprises acrylic acid cross-linked with divinyl glycol;

Pemulen™ polymers which comprise acrylic acid and C₁₀₋₃₀alkyl acrylatecross-linked with allyl pentaerythritol (e.g., TR-1 NF, TR-2 NF); and

Ashland™ carbomers which comprise cross-linked polyacrylic acid (e.g.,Ashland™ 940, 941, 980, and 981 carbomers).

In some embodiments, the polyacrylic acid(s) may have a certain averagemolecular weights (e.g., M_(n), M_(w)). As known to those of ordinaryskill in the art, the number average (M_(n)) and weight average (M_(w))are defined by the corresponding equations below, where N_(i) is thenumber of molecules of each polymer species and M_(i) is the molar massof that polymer species.

${M_{n} = \frac{\sum{M_{i}N_{i}}}{\sum N_{i}}},{M_{w} = \frac{\sum{M_{i}^{2}N_{i}}}{\sum{M_{i}N_{i}}}},$

In some embodiments, the number and/or weight average molecular weightof one or more polyacrylic acid may be greater than or equal to about400,000 g/mol, greater than or equal to about 500,000 g/mol, greaterthan or equal to about 750,000 g/mol, greater than or equal to about1,000,000 g/mol, greater than or equal to about 1,500,000 g/mol, greaterthan or equal to about 2,000,000 g/mol, greater than or equal to about3,000,000 g/mol, greater than or equal to about 4,000,000 g/mol, greaterthan or equal to about 5,000,000 g/mol, greater than or equal to about6,000,000 g/mol, greater than or equal to about 7,000,000 g/mol, orgreater than or equal to about 8,000,000,000 g/mol. In some instances,the number and/or weight average molecular weight of one or morepolyacrylic acid may be less than or equal to about 3,000,000,000 g/mol,less than or equal to about 1,000,000,000 g/mol, less than or equal toabout 8,000,000 g/mol, less than or equal to about 6,00,000 g/mol, lessthan or equal to about 5,000,000 g/mol, less than or equal to about4,000,000 g/mol, less than or equal to about 3,000,000 g/mol, less thanor equal to about 2,500,000 g/mol, less than or equal to about 2,000,000g/mol, less than or equal to about 1,500,000 g/mol, less than or equalto about 1,000,000 g/mol, or less than or equal to about 750,000 g/mol.It should be understood that all combinations of the above-referencedranges are possible (e.g., greater than or equal to about 400,000 g/moland less than or equal to about 1,000,000,000 g/mol). Other values ofnumber average molecular weight are possible. The average molecularweights (e.g., M_(n), M_(w)) described herein were measured using a gelpermeation chromatography (GPC).

In some embodiments, the adhesive matrix comprises at least two (ormore, e.g., two, three, four, five, six, seven, eight, nine, or ten, ormore) different polyacrylic acids which, when mixed together and applied(e.g., to a biological tissue), as described according to certainembodiments herein, lead to an unexpectedly large increase in adhesiveand/or mechanical behavior.

In some embodiments, an adhesive matrix may comprise a first polyacrylicacid and second polyacrylic acid. It is generally understood that thefirst polyacrylic acid and the second polyacrylic acid are differentpolyacrylic acids, e.g., comprise different components within theirstructures (e.g., type of cross-linking moiety, degree of cross-linking,chemical structure). In some embodiments, the first polyacrylic acid andthe second polyacrylic acid can comprise different components withintheir respective polymeric backbones. In certain embodiments, the firstand second polyacrylic acids comprise one or more different repeat unitsand/or are each chemically synthesized from different monomers. In someembodiments, the first and second polyacrylic acids do not differ in thebackbone structure. In some such embodiments, the first and secondpolyacrylic acids may differ in the degree of cross-linking, molecularweight, and/or the cross-linking moiety.

Exemplary monomers that the polyacrylic acids, described herein, may besynthesized from include, but are not limited to:

wherein R¹ is optionally substituted C₁₋₅₀alkyl, e.g., optionallysubstituted C₁₀₋₃₀alkyl.

In certain embodiments, a polyacrylic acid comprises an acrylic acidmonomer:

In certain embodiments, a polyacrylic acid comprises an acrylic acidmonomer and a corresponding ester monomer:

wherein R¹ is optionally substituted C₁₋₅₀alkyl, e.g., optionallysubstituted C₁₀₋₃₀alkyl.

In certain embodiments, at least one polyacrylic acid is a polymer ofacrylic acid and/or acrylic acid ester cross-linked with divinyl glycol.In certain embodiments, at least one polyacrylic acid is a polymer ofacrylic acid and/or acrylic acid ester cross-linked with allylpentaerythritol. In certain embodiments, at least one polyacrylic acidis a polymer of acrylic acid and/or acrylic acid ester cross-linked withallyl sucrose.

In some embodiments, the first polyacrylic acid is biodegradable. Incertain embodiments, the second polyacrylic acid is biodegradable.

In certain embodiments, the first and/or second polyacrylic acidscomprise a Carbopol® polymer, e.g., a Carbopol® homopolymer, a Carbopol®copolymer, or a Carbopol® interpolymer. In some embodiments, the firstand/or second polyacrylic acids comprise a polycarbophil polymer, e.g.Noveon® AA-1 Polycarbophil. In some embodiments, the first polyacrylicacid comprises a Carbopol® homopolymer, e.g., Carbopol®974P NF, whilethe second polyacrylic acid comprises a polycarbophil polymer, e.g.Noveon® AA-1 Polycarbophil.

In certain embodiments, the first and/or second polyacrylic acidscomprise carbomer homopolymers. In some embodiments, the first and/orsecond polyacrylic acids comprise polycarbophils. In some embodiments,the first polyacrylic acid comprises a carbomer homopolymer while thesecond polyacrylic acid comprises a polycarbophil.

In some embodiments in which the adhesive matrix comprises more than onepolyacrylic acid, the weight percentage of a single type of polyacrylicacid may be greater than or equal to about 1 wt. %, greater than orequal to about 5 wt. %, greater than or equal to about 10 wt. %, greaterthan or equal to about 15 wt. %, greater than or equal to about 20 wt.%, greater than or equal to about 25 wt. %, greater than or equal toabout 30 wt. %, greater than or equal to about 35 wt. %, greater than orequal to about 40 wt. %, greater than or equal to about 45 wt. %,greater than or equal to about 50 wt. %, greater than or equal to about55 wt. %, greater than or equal to about 60 wt. %, greater than or equalto about 65 wt. %, greater than or equal to about 70 wt. %, greater thanor equal to about 75 wt. %, greater than or equal to about 80 wt. %,greater than or equal to about 85 wt. %, greater than or equal to about90 wt. %, greater than or equal to about 95 wt. %, or greater than orequal to about 98%. In some instances, the weight percentage may be lessthan or equal to about 100 wt. %, less than or equal to about 95 wt. %,less than or equal to about 90 wt. %, less than or equal to about 85 wt.%, less than or equal to about 80 wt. %, less than or equal to about 75wt. %, less than or equal to about 70 wt. %, less than or equal to about65 wt. %, less than or equal to about 60 wt. %, less than or equal toabout 55 wt. %, less than or equal to about 50 wt. %, less than or equalto about 45 wt. %, less than or equal to about 40 wt. %, less than orequal to about 35 wt. %, less than or equal to about 30 wt. %, less thanor equal to about 25 wt. %, less than or equal to about 20 wt. %, orless than or equal to about 15 wt. %. Combinations of the abovereferenced ranges are also possible (e.g., greater than or equal to 30wt. % and less than or equal to about 100 wt. %, greater than or equalto 50 wt. % and less than or equal to about 100 wt. %). The weightpercentage may be determined as described above.

The first polyacrylic acid and the second polyacrylic acid may bepresent in the adhesive matrix and/or composition in any suitable massratio. In some embodiments, the mass ratio of the first polyacrylic acidto the second polyacrylic acid within the adhesive matrix and/orcomposition is from about 1:10 to about 10:1. In some embodiments, themass ratio of the first polyacrylic acid to the second polyacrylic acidwithin the adhesive matrix and/or composition is equal to or greaterthan 1:9, equal to or greater than 1:8, equal to or greater than 1:7,equal to or greater than 1:6, equal to or greater than 1:5, equal to orgreater than 1:4, equal to or greater than 1:3, equal to or greater than1:2, equal to or greater than 1:1.5, or equal to or greater than 1:1.2.In some instances, the mass ratio of the first polyacrylic acid to thesecond polyacrylic acid within the adhesive matrix and/or composition isequal to or less than 9:1, equal to or less than 8:1, equal to or lessthan 7:1, equal to or less than 6:1, equal to or less than 5:1, equal toor less than 4:1, equal to or less than 3:1, equal to or less than 2:1,equal to or less than 1.5:1, or equal to or less than 1.2:1.Combinations of the above-referenced ranges are also possible (e.g.,equal to or greater than 1:10 and less than 10:1).

As noted above, certain embodiments relate to inventive adhesivecompositions. The adhesive compositions can be used, according tocertain embodiments, with substrates (e.g., small intestine submucosa,fibrin-containing substrates, or other substrates), for example, to formtissue patches. It should be understood that the use of the adhesivecompositions described herein is not limited to tissue patches, and theadhesives may have other uses.

FIG. 1A is a perspective-view schematic illustration of exemplaryarticle 100 comprising substrate 110 and an adhesive matrix 112associated with substrate 110. In certain embodiments, the substrate andadhesive matrix can be configured to be applied to tissue such that theadhesive matrix contacts the tissue. In some embodiments, adhesivematrix 112 is substantially free of loose powder (i.e., it containsloose powder in an amount of less than about 0.1 wt. %, less than about0.01 wt. %, less than about 0.001 wt. %, or it contains no loosepowder).

In certain embodiments, the adhesive matrix can help to achieveimmobilization of the overlying substrate on a surface, such as a tissuesurface. For example, in some embodiments, adhesive matrix 112 can beconfigured to enhance the degree to which substrate 110 is immobilizedon a tissue surface onto which substrate 110 and adhesive matrix 112have been applied. In some instances, immobilization of the substratecan be achieved without the need to apply much or any external pressure.In certain embodiments, immobilization of the substrate can be achievedin fewer than 5 minutes, fewer than 120 seconds, fewer than 60 seconds,or fewer than 30 seconds. In certain embodiments, once the substrate hasbeen immobilized, it may remain in place for at least 12 hours, at least24 hours, at least 48 hours, or at least 72 hours (and/or, in someembodiments, up to 30 days, up to 120 days, and/or until the substratebiodegrades).

In certain embodiments, the adhesive can be selected or configured suchthat it does not form covalent chemical bonds with the underlyingsurface to which it is applied (e.g., an underlying tissue surface). Incertain embodiments, the adhesive matrix can be selected or configuredto interact with the surface to which it is applied (e.g., a tissuesurface) via hydrogen bonding and/or van der Waals forces. In someembodiments the adhesive matrix can be configured to interact with theunderlying surface (e.g., tissue surface) via physisorption (sometimesalso referred to as adhesive dispersion). Such adhesives can beadvantageous, for example, when used to adhere tissue, at least in partbecause, while they effectively immobilize the patch on the tissue, theydo not form strong (or permanent) bonds, which can lead to tissuedamage. Of course, while non-covalently bound adhesive matrices havebeen described, it should be understood that the invention is notlimited to the use of such adhesives, and in other cases, adhesives thatcovalently bond to underlying surfaces (e.g., tissue surfaces) can beemployed.

In some embodiments, the substrate can be applied to a tissue surfaceand can be allowed to integrate with the underlying tissue.

The adhesive matrix can be applied to or otherwise associated with thesubstrate via the methods, described herein. In other embodiments, theadhesive matrix can be formed on another substrate, removed from thesubstrate on which it is formed, and subsequently applied to a differentsubstrate, prior to applying the adhesive matrix to tissue.

While FIG. 1A illustrates an embodiment in which an adhesive matrix isapplied to one side of a substrate, in certain embodiments, adhesivematrix can be applied to multiple sides of the substrate. For example,in FIG. 1B, adhesive matrix 112A and 112B are arranged on opposite sidesof substrate 110. When arranged in this fashion, the substrate andadhesive can be used to join two surfaces, with a first surface adheringto adhesive matrix 112A and a second surface adhering to adhesive matrix112B. For example, substrates with adhesive applied on both sides can beused to join two surfaces of skin, a pleural space, spaces between bonetissue surfaces, and other such cavities within a body.

In certain cases, and as described in more detail below, the substratecan comprise fibrin, tissue (e.g., small intestine submucosa), syntheticpolymers, cellulose, diaphragm, porcine skin, bovine skin, human skin,pericardium, extracellular matrix collagen, or amnion. In some suchembodiments, the adhesive matrix is configured to immobilize thesubstrate (e.g., by anchoring the substrate to the tissue to which it isapplied) and provide support while fibrinogen and/or fibrin from thetissue integrates with the fibrin and/or fibrinogen within thesubstrate. For example, fibrinogen and/or fibrin within the tissue canmigrate from the tissue, through the adhesive, and into the substrate,where the fibrinogen and/or fibrin from the tissue can polymerize and/orcross-link with fibrinogen and/or fibrin within the substrate. Theintegration of the fibrin and/or fibrinogen within a subject's tissuewith the fibrin and/or fibrinogen within the substrate can lead to theformation of a more robust interface and/or integration region betweenthe tissue, the adhesive, and the substrate, which can produce enhancedtissue repair.

Certain embodiments employ substrates (including fibrin-containingsubstrates and other substrates) having low liquid (e.g., low water)content. For example, in some embodiments, the substrate has a liquidcontent of less than about 20 wt %, less than about 15 wt %, less thanabout 12 wt %, or less than about 10 wt %. In some embodiments, thesubstrate has a water content of less than about 20 wt %, less thanabout 15 wt %, less than about 12 wt %, or less than about 10 wt %. Suchsubstrates may, according to certain embodiments, have any of the fibrincontents and/or compositional properties described elsewhere herein.

While the present invention is not limited to the use of substrates madeof any particular materials, certain embodiments relate tofibrin-containing substrates. In some embodiments, the substrate has acombined fibrin and fibrinogen content of at least about 50 wt. %, atleast about 75 wt. %, at least about 80 wt. %, at least about 85 wt. %,or at least about 90 wt. %. In some embodiments, the substrate has afibrin content of at least about 50 wt. %, at least about 75 wt. %, atleast about 80 wt. %, at least about 85 wt. %, or at least about 90 wt.%.

Fibrin-containing substrates with low amounts of water can befabricated, for example, by exposing a solid matrix comprising water andfibrin to a dehydrating agent (e.g., a dehydrating liquid) such thatwater is displaced or otherwise removed from the solid matrix. In somesuch embodiments, at least a portion (or all) of the water within thesolid matrix can be displaced and/or otherwise removed by thedehydrating agent, resulting in a substrate with a relatively low watercontent. A variety of dehydrating agents can be used in association withsuch methods. Examples of liquid dehydrating agents that can be usedinclude, but are not limited to, non-polar liquids (e.g., pentane,cyclopentane, hexane, cyclohexane, benzene, 1,4-Dioxane, chloroform, anddiethyl ether); polar aprotic liquids (e.g., dichloromethane (DCM),tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF),acetonitrile, dimethyl sulfoxide (DMSO), and propylene carbonate); polarprotic liquids (e.g., formic acid, butanol, isopropanol, propanol,ethanol, methanol, acetic acid, and nitromethane). and/or others (e.g.,butylacetate, chlorobenzene, diethylether, diisoproylether,ethylmethylketone, heptane, isoamylalcohol, pentachloroethane,tetracholoethane, tetrachloromethane, toluene, and xylene).

Fibrin-containing substrates (e.g., patches) can be manufactured using avariety of suitable methods. In some embodiments, fibrin-containingsubstrates (e.g., patches) are made by applying a compressive force to aliquid-containing composition comprising fibrinogen (and/or fibrin)between two surfaces (e.g., within a syringe or other chamber). A filtercan be placed within or near the volume in which the compressive forceis applied to the liquid-containing composition such that unwantedmaterial (e.g., some liquid components (e.g., water), blood cells, etc.)is passed through the filter while desirable components (e.g., fibrinand/or fibrinogen) are retained by the filter to form thefibrin-containing substrate. In this way, the concentration of fibrin(and/or fibrinogen) can be increased, potentially substantially, as thecompressive force is applied to the liquid-containing composition. Inaddition, in some embodiments, at least a portion of the fibrinogenand/or fibrin can chemically react (e.g., the fibrinogen can polymerizeto form fibrin and/or the fibrin can cross-link) before, during, and/orafter application of the compressive force. Reaction and concentrationvia application of the compressive force (e.g., by removing at least aportion of the non-fibrin and/or non-fibrinogen components, such asliquid components (e.g., water), blood cells, and the like) can lead tothe formation of a highly-concentrated, mechanically robust substrate(e.g., patch) that can be handled relatively easily and provide goodstructural reinforcement at a wet site, such as a bleeding wound. Incertain embodiments, additional advantage, economy, convenience, and/orsafety is gained by the use of autologous whole blood as theliquid-containing composition to which a compressive force is applied toform the substrate (e.g., patch). Examples of such methods aredescribed, for example, in International Patent Application PublicationNo. WO 2013/116633, filed Feb. 1, 2013, published on Aug. 8, 2013, andentitled “Tissue Patches and Associated Systems, Kits, and Methods”;U.S. Patent Publication No. US 2013/0202656, filed Oct. 4, 2012,published on Aug. 8, 2013, and entitled “Systems and Kits for theFabrication of Tissue Patches”; U.S. Patent Publication No. US2013/0202674, filed on Oct. 4, 2012, published on Aug. 8, 2013, andentitled “Tissue Patch”; and U.S. Patent Publication No. US2013/0202675, filed Oct. 4, 2012, published on Aug. 8, 2013, andentitled “Systems and Methods for the Fabrication of Tissue Patches,”each of which is incorporated herein by reference in its entirety forall purposes.

In some embodiments, the substrate can contain relatively highlycross-linked fibrin. Highly cross-linked fibrin can be achieved, forexample, by including a cross-linking agent (e.g., thrombin, FactorXIII, and/or calcium-containing compounds, and the like) during theformation of the substrate. One of ordinary skill in the art would becapable of determining the amount of cross-linking in a givenfibrin-containing medium by using one exemplary screening test in whichthe fibrin-containing medium is submerged in an aqueous solution of 8molar (i.e., 8M) urea and maintained at a temperature of 25° C. Undersuch conditions, samples containing highly cross-linked fibrin can takea relatively long time to dissolve, while samples containing slightlycross-linked fibrin (or fibrin that is not cross-linked at all) can bedissolved relatively quickly. In certain embodiments, upon submergingthe fibrin-containing substrate in an 8M aqueous solution of urea at 25°C., the fibrin-containing portion will retain its structural integrity(i.e., less than 50 wt % of the portion will dissociate) over a periodof at least about 2 hours, at least about 8 hours, at least about 24hours, at least about 48 hours, at least about 72 hours, at least about1 week, or at least about 1 month (and/or, up to about 1 year, orlonger). In certain embodiments, upon submerging the fibrin-containingsubstrate in a 6M aqueous solution of urea at 25° C., thefibrin-containing portion will retain its structural integrity (i.e.,less than 50 wt % of the portion will dissociate) over a period of atleast about 2 hours, at least about 8 hours, at least about 24 hours, atleast about 48 hours, at least about 72 hours, at least about 1 week, orat least about 1 month (and/or, up to about 1 year, or longer). Ofcourse, the fibrin-containing substrate described herein can also bedesigned to include fibrin that is cross-linked to a less substantialdegree, and in some cases, to include fibrin that is not cross-linked.In certain embodiments, the conditions under which the substrate isformed can be selected such that the final substrate includes thedesired degree of cross-linking, for example, by adding an appropriateamount of cross-linking agent to the liquid medium to which acompressive force is to be applied.

In certain embodiments, the substrates (e.g., fibrin-containingsubstrates) can have relatively high tensile strengths. In someembodiments, the substrate has a tensile strength of at least about 175kPa, at least about 250 kPa, at least about 500 kPa, at least about 600kPa, or between about 175 kPa and about 650 kPa, when measured as a truestress at break.

In certain embodiments, the substrate component (e.g., afibrin-containing substrate component) can maintain its strength and/orflexibility after sterilization. For example, in some embodiments, thesubstrate component has a Young's modulus of about 10 GPa or less, ofabout 1 GPa or less, or of about 100 kPa or less after sterilizationusing gamma radiation at an intensity of 30 kGy. In some embodiments,the substrate material has a Young's modulus of from about 1 kPa toabout 10 GPa, of from about 1 kPa to about 1 GPa, or of from about 1 kPato about 100 kPa after sterilization using gamma radiation at anintensity of 30 kGy.

In certain embodiments, the substrate (e.g., substrate 110 in FIG. 1A)is biodegradable. In certain embodiments, the biodegradable materialsdescribed herein (e.g., in the substrate and/or in the adhesive) can bebroken down such that less than 2 wt %, less than 1 wt %, less than 0.1wt %, or less than 0.01 wt % of their mass remains in a subject (e.g., ahuman subject) after fewer than 365 days, fewer than 180 days, fewerthan 90 days, fewer than 60 days, or fewer than 30 days of being locatedwithin the subject.

In certain embodiments, the substrate is substantially free of thrombin.An article (e.g., a substrate such as a fibrin-containing substrate, apatch, an adhesive material, etc.) is said to be “substantially free ofthrombin” when the article contains thrombin in an amount of less thanor equal to 0.0025 wt %. In some embodiments, an article that issubstantially free of thrombin contains thrombin in an amount of lessthan or equal to 0.001 wt %, less than or equal to 0.00025 wt %, or lessthan or equal to 0.0001 wt %. In some embodiments, an article that issubstantially free of thrombin is completely free of thrombin. In someembodiments, an article that is substantially free of thrombin is alsosubstantially free of prothrombin (i.e., it contains prothrombin in anamount of less than or equal to 0.0025 wt %). In some embodiments, anarticle that is substantially free of thrombin and/or prothrombincontains prothrombin in an amount of less than or equal to 0.001 wt %,less than or equal to 0.00025 wt %, or less than or equal to 0.0001 wt%. In some embodiments, an article that is substantially free ofthrombin and/or prothrombin is completely free of prothrombin. However,the invention is not strictly limited to thrombin-free applications, andin other embodiments, thrombin can be mixed in with and/or coated on theadhesive matrices.

As illustrated in FIG. 1A, substrate 110 (which can be, for example, asolid matrix) is in the form of a cylindrical disc with a substantiallycircular cross-sectional geometry. In other embodiments, the substrate(or the entire article, including both substrate and adhesive matrix)can have other cross-sectional geometries such as, for example,substantially elliptical, polygonal (e.g., including any number of sidessuch as in the form of a triangle, a quadrilateral (e.g., rectangular orsubstantially square), etc.), irregularly-shaped, or any other suitableshape.

In some embodiments, the substrate (e.g., substrate 110), adhesivematrix (112) and/or article (e.g., article 100) can be in the form of asheet or film. For example, the substrate and/or article may have anaspect ratio (measured as the ratio of the maximum cross-sectionaldimension to the minimum thickness of the substrate or article, forexample, upon inspection) of at least about 5:1, at least about 10:1,between about 5:1 and about 100:1, or between about 5:1 and about 50:1.In certain embodiments, the substrate and/or article has an averagethickness of between about 500 microns and about 1 cm. The averagethickness of a component can be determined by measuring the thickness ofthe component at a representative number of locations and numberaveraging the results. In certain embodiments, the substrate and/orarticle has at least one cross-sectional dimension of at least about 1cm, at least about 10 cm, at least about 50 cm, or greater. As oneparticular example, the substrate comprises a disc (e.g., asubstantially cylindrical disc) with a thickness of between about 500microns and about 1 cm, and a maximum cross-sectional diameterorthogonal to the thickness that is at least about 1 cm, at least about10 cm, at least about 50 cm, or greater.

The adhesive matrix and the substrate can be in contact, either directly(i.e., in direct contact) or indirectly (i.e., in indirect contact), incertain embodiments. For example, as illustrated in FIG. 1A, substrate110 and adhesive matrix 112 are in direct contact. However, in otherembodiments, one or more solid intermediate materials can be positionedbetween the substrate and the adhesive matrix such that the substrateand the adhesive matrix do not contact each other directly, in whichcase, the substrate and the adhesive matrix would be said to be inindirect contact. Both articles in direct contact with each other andarticles in indirect contact with each other are considered to be incontact with each other, as described herein.

In certain embodiments, adhesive matrix 112 comprises a water activatedpolymeric adhesive. Those of ordinary skill in the art are familiar withwater-activated polymeric adhesives, which are adhesive polyacrylicacids that are rendered tacky by application of water. One can use awater-activated polymeric adhesive by applying water just prior to use,or by relying on water at the application site, to render the adhesivetacky.

Any suitable water-activated polymeric adhesive can be used. In someembodiments, the water-activated polymeric adhesive comprises any of theadhesive compositions described above that would be activated upon theapplication of water.

In general, the adhesive matrix may have any suitable shape ordimension. In some embodiments, the dimensions of the adhesive matrixmay be selected as desired. It should be understood that the adhesivematrix can have any suitable cross-sectional dimension. For instance, insome embodiments, adhesive matrix may have a maximum cross-sectionaldimension of greater than or equal to about 0.01 cm, greater than orequal to about 0.05 cm, greater than or equal to about 0.1 cm, greaterthan or equal to about 1 cm, greater than or equal to about 2 cm,greater than or equal to about 5 cm, greater than or equal to about 10cm, greater than or equal to about 20 cm, greater than or equal to about30 cm, greater than or equal to about 40 cm, greater than or equal toabout 50 cm, greater than or equal to about 60 cm, greater than or equalto about 70 cm, greater than or equal to about 80 cm, or greater than orequal to about 90 cm. In some instances, an adhesive matrix, may have amaximum cross-sectional dimension of less than or equal to about 100 cm,less than or equal to about 90 cm, less than or equal to about 80 cm,less than or equal to about 70 cm, less than or equal to about 60 cm,less than or equal to about 50 cm, less than or equal to about 40 cm,less than or equal to about 30 cm, less than or equal to about 20 cm,less than or equal to about 10 cm, or less than or equal to about 5 cm.Combinations of the above-referenced ranges are also possible (e.g.,greater than or equal to about 1 cm and less than or equal to about 100cm). Other values of maximum cross-sectional dimensions are alsopossible.

In some cases, at least one or at least two cross-sectional dimensions(e.g., a length and a width) of the adhesive matrix may be greater thanor equal to about 0.01 cm, greater than or equal to about 0.05 cm,greater than or equal to about 0.1 cm, greater than or equal to about 1cm, greater than or equal to about 2 cm, greater than or equal to about5 cm, greater than or equal to about 10 cm, greater than or equal toabout 20 cm, greater than or equal to about 30 cm, greater than or equalto about 40 cm, greater than or equal to about 50 cm, greater than orequal to about 60 cm, greater than or equal to about 70 cm, greater thanor equal to about 80 cm, or greater than or equal to about 90 cm. Insome instances, at least one or at least two cross-sectional dimensionsof adhesive matrix may be less than or equal to about 100 cm, less thanor equal to about 90 cm, less than or equal to about 80 cm, less than orequal to about 70 cm, less than or equal to about 60 cm, less than orequal to about 50 cm, less than or equal to about 40 cm, less than orequal to about 30 cm, less than or equal to about 20 cm, less than orequal to about 10 cm, or less than or equal to about 5 cm. Combinationsof the above-referenced ranges are also possible (e.g., greater than orequal to about 1 cm and less than or equal to about 100 cm). Othervalues are also possible.

In some embodiments, the adhesive matrix may be relatively thin. In someembodiments, the thickness of the adhesive matrix may be less than orequal to about 1 mm, less than or equal to about 0.9 mm, less than about0.8 mm, less than or equal to about 0.7 mm, less than or equal to about0.6 mm, less than or equal to about 0.5 mm, less than or equal to about0.4 mm, less than or equal to about 0.3 mm, less than or equal to about0.2 mm, less than or equal to about 0.1 mm, less than or equal to about0.09 mm, or less than or equal to about 0.08 mm. In some instances, thethickness of the adhesive matrix may be greater than or equal to about0.03 mm, greater than or equal to about 0.04 mm, greater than or equalto about 0.05 mm, greater than or equal to about 0.06 mm, greater thanor equal to about 0.07 mm, greater than or equal to about 0.08 mm,greater than or equal to about 0.09 mm, greater than or equal to about0.1 mm, greater than or equal to about 0.2 mm, greater than or equal toabout 0.3 mm, greater than or equal to about 0.4 mm, greater than orequal to about 0.5 mm, or greater than equal to 0.6 mm. Combinations ofthe above-referenced ranges are possible (e.g., greater than or equal toabout 0.03 mm and less than or equal to about 1 mm, greater than orequal to about 0.5 mm and less than or equal to about 1 mm). Othervalues of thickness of the adhesive matrix are possible. The thicknessmay be measured using a micrometer. One of ordinary skill in the artwould be knowledge of thickness measurements.

In some embodiments, a pharmaceutically active composition, growthfactor, or other bioactive composition can be applied to a surface ofand/or included within the bulk of one or more regions of any of thearticles described herein (e.g., substrate 110 and/or adhesive matrix(s)112 in FIG. 1A). In certain embodiments, one or more pharmaceuticallyactive compositions can be included within and/or on a surface of thearticles (e.g., adhesive matrices, substrates) described herein. In somesuch embodiments, the article can act as a delivery mechanism for thepharmaceutically active composition. Exemplary pharmaceutically activecompositions that be used in association with the articles describedherein include, but are not limited to, analgesics, antimicrobial agents(e.g., antibiotics, antifungal, and/or antiviral agents), hormones,insulin, vitamins, and the like. In certain embodiments, thepharmaceutically active composition comprises a small molecule (i.e., amolecule with a molecular weight of less than about 2000 g/mole and, insome instances, less than about 1000 g/mole or less than about 500g/mole). Exemplary small molecules include, for example, nucleic acids,peptides, polypeptides, peptide nucleic acids, peptidomimetics,carbohydrates, lipids or other organic (carbon containing) or inorganicmolecules. In certain embodiments, the pharmaceutically activecomposition is selected from “Approved Drug Products with TherapeuticEquivalence and Evaluations,” published by the United States Food andDrug Administration (F.D.A.) (the “Orange Book”).

In certain embodiments, an antimicrobial agent can be applied to asurface of and/or included within the bulk of one or more regions of anyof the articles described herein (e.g., substrate 110 and/or adhesivematrix 112 in FIG. 1A). The use of antimicrobial agents or other drugscan be advantageous for a variety of reasons. For example, a growingconcern with the use of certain tissue sealants is that the tissuesealant can capture or contain bacteria within or under the surface ofthe tissue sealant and create an environment in which bacteria can grow.Including an antimicrobial agent within one or more surfaces or volumesof the article can help to combat the growth of bacteria on or aroundthe site to which the article is applied.

A variety of antimicrobial agents can be incorporated into any of thearticles described herein (e.g., substrate 110 and/or adhesive matrix(s)112 in FIG. 1A). The antimicrobial agent may be bacteriocidal,virucidal, fungicidal, and/or any combination thereof. In certainembodiments, a zinc-containing material such as a zinc oxide can be usedas an antimicrobial agent. Examples of suitable antimicrobial agentsthat can be used include, but are not limited to, metal-containingcompounds (e.g., zinc-containing compounds, silver-containing compounds(e.g., silver nitrate, silver sulfadiazine, silver foams, flammacerium,Acticoat 7, Aquacel-Ag, Silvercel, and/or silver amniotic membrane),gold-containing compounds, copper-containing compounds, tin-containingcompounds, chromium-containing compounds, and the like), organicantimicrobial compounds (e.g., organic antibiotics such as tetracyclineantibiotics, rifampin, minocycline, and the like), antimicrobialpeptide(s) (e.g., defensins, histone H1.2, cecropin B, recombinantbactericidal/permeability-increasing protein (rBPI), and/or ceragenins),chitosan, topical antibiotics (e.g., mafenide acetate, bacitracin,mupirocin, Neosporin®, polymyxin B, nitrofurazone, and/or nystatin),iodine-based compounds (e.g., povidone-iodine, cadexomer iodine,liposomal iodine, and/or Repithel®, and/or Iocide™), and the like. Otheragents that can be added to the tissue patches described herein includechlorhexidine, superoxidized water, acidified nitrite, p38MAPKinhibitor, probiotic Lactobacillus, honey, essential oils, and/orpapaya.

In some embodiments, one or more growth factors can be included inand/or on a surface of any of the articles described herein (e.g.,substrate 110 and/or adhesive matrix(s) 112 in FIG. 1A). Such growthfactors can contribute to hemostasis, tissue healing, or otherbiological processes. For example, in certain embodiments, PlateletDerived Growth Factor (PDGF) can be included within and/or on a surfaceof an article (e.g., in or on substrate 110 and/or in or on adhesivematrix(s) 112 in FIG. 1A), which can assist in wound healing. Otherexamples of growth factors that be included include, but are not limitedto, growth factors from one or more of the following families:adrenomedullin (AM), angiopoietin (Ang), autocrine motility factor, bonemorphogenetic proteins (BMPs), brain-derived neurotrophic factor (BDNF),epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growthfactor (FGF), glial cell line-derived neurotrophic factor (GDNF),granulocyte colony-stimulating factor (G-CSF), granulocyte macrophagecolony-stimulating factor (GM-CSF), growth differentiation factor-9(GDF9), hepatocyte growth factor (HGF), hepatoma-derived growth factor(HDGF), insulin-like growth factor (IGF), migration-stimulating factor,myostatin (GDF-8), nerve growth factor (NGF) and other neurotrophins,thrombopoietin (TPO), transforming growth factor alpha (TGF-α),transforming growth factor beta (TGF-β), tumor necrosis factor-alpha(TNF-α), vascular endothelial growth factor (VEGF), placental growthfactor (PlGF), and the like.

In certain embodiments, a backing layer can be applied to any of thearticles described herein (e.g., substrate 110 and/or adhesive matrix(s)112 in FIG. 1A). However, it should be understood that backing layersare not required, and in some but not necessarily all embodiments can beadvantageous to omit.

As noted elsewhere, certain of the articles described herein (e.g.,adhesive matrices) can be used as tissue patches. In certainembodiments, a tissue patch can be assembled and/or used as follows. Asubstrate can be formed and an adhesive matrix can be placed on thesubstrate. In some embodiments, the assembled patch can be applied to atissue surface (e.g., such that the adhesive matrix contacts the tissuesurface).

Once applied to a tissue site, blood from the subject can naturallystart the coagulation process. In some embodiments, the adhesive matrixcan provide an adhesive anchor material that holds the patch in placeover the tissue, even when it is bleeding.

Any of the articles described herein (e.g., a substrate, adhesivematrix(s), and/or combinations of substrates and adhesives matrix) canbe packaged, according to certain embodiments. For example, in someembodiments, a substrate and/or adhesive(s) may be packaged within afoil pouch or other suitable container. In some embodiments, thecontainer within which the article is packaged is sealed. Packaging theproducts described herein can allow one to store them for future use.The adhesive composition can be used to produce a patch that issubsequently sterilized and packaged (and optionally stored for days,weeks, months, or longer) for application to a subject at a locationremote from the patch production location.

In certain embodiments, the article within the package is sterile (e.g.,by sterilizing the article prior to packaging the article).

In certain embodiments, the articles described herein can have arelatively long shelf life. In some embodiments, the adhesives describedherein can be packaged and stored at room temperature for a period of atleast 1 month, at least 6 months, or at least 1 year without losing asubstantial amount (i.e., 5%) of its adhesive properties. In addition,the components used to make certain of the articles described herein(e.g., substrates, adhesives, and/or patches) can have a relatively longshelf life, especially when enclosed in a sterile package.

The articles (e.g., adhesives, substrates, combinations of the two,etc.) described herein can be used in a wide variety of applicationsincluding, for example, general surgery, vascular surgery, spine surgeryand ophthalmologic surgery. The articles can be configured to be appliedto any type of tissue including soft tissue, bone tissue, or any othertype of tissue. The articles can be employed to: assist hemostasis in ableeding area, reduce blood flow from solid organs, assist in sealingsuture holes, assist in sealing anastomosis or leaks from hollow organs,assist or replace sutures in surgical procedures (particularly wheresuturing is difficult or impossible), produce a water-tight closureacross portions of tissue (e.g., across a suture line), reinforce tissue(e.g., in reinforcing suture lines including high stress suture lines),perform of tissue approximation, replace sutures, fill dead space orother voids in tissue, and/or in vascular repair (e.g., to seal avascular defect). In certain embodiments, certain of the articlesdescribed herein can be employed to perform gastrointestinal suture linereinforcement, in preventing the formation of seroma (e.g., aftersurgical procedures), for use as soft tissue (e.g., after breast canceror other surgical procedures in which tissue may be removed), as burndressings, and/or for combined hemostasis/sealing and drug delivery.

In some embodiments, certain of the articles described herein (e.g.,adhesives, substrates, combinations of the two, etc.) can be used totreat spleen tissue, for example, to inhibit or stop bleeding or theleaking of other bodily fluids and/or to partially or completely fillvoid(s) in the spleen. In certain embodiments, certain of the articlesdescribed herein can be used to treat lung tissue, for example, toinhibit, or stop bleeding or the leaking of other bodily fluids, topartially or completely fill void(s) in the lung, and/or to inhibit orstop the leaking of air from the internal cavity of a lung. In someembodiments, certain of the articles described herein can be used totreat the liver, for example, to inhibit or stop bleeding or the leakingof other bodily fluids from the liver and/or to partially or completelyfill void(s) in the liver. In certain embodiments, certain of thearticles described herein can be used to treat heart tissue, forexample, to inhibit or stop bleeding or the leaking of other bodilyfluids, to partially or completely fill void(s) in the heart orassociated blood vessels, and/or to inhibit or stop the leaking of bloodfrom an internal cavity of a heart. Certain of the articles describedherein can also be used to treat tissues in or near the gastrointestinaltract, for example, to inhibit, or stop bleeding or the leaking of otherbodily fluids, to partially or completely fill void(s) ingastrointestinal tissues.

The articles described herein can have a variety of advantageousproperties, in certain although not necessarily all embodiments. Forexample, certain embodiments of the fibrin-containing substratesdescribed herein can be formed and applied at the site of application.Also, as noted above, articles formed according to certain embodimentsof the methods described herein can have relatively high tensilestrengths. Moreover, some embodiments of the articles described hereinare capable of adhering to a wet (e.g., bleeding) tissue surface.

Certain of the substrates, adhesives, and tissue patches describedherein can be biocompatible and/or biodegradable. In addition, thesubstrates, adhesives, and/or tissue patches can be configured such thatthey do not interfere with any metabolic pathways that would producesignificant biologic dysfunction. The use of sterile materials andcomponents to form certain embodiments of the articles described hereincan reduce or eliminate the risk of bacterial, viral, or otherinfectious agents being transmitted as the result of the use of thearticle.

The articles described herein (e.g., substrates, adhesives, tissuepatches, etc.) can be used to treat human subjects, in certainembodiments. In other embodiments, the articles described herein can beused to treat non-human animal subjects. For example, in certain cases,the articles described herein can be used in veterinary applications,for example, those involving horses, dogs, cats, and the like.

The following patent publications are incorporated herein by referencein their entirety for all purposes: International Patent ApplicationSerial No. PCT/US2013/024322 filed Feb. 1, 2013, published asInternational Patent Publication No. WO 2013/116633 on Aug. 8, 2013, andentitled “Tissue Patches and Associated Systems, Kits, and Methods”;U.S. patent application Ser. No. 13/644,868 filed Oct. 4, 2012,published as U.S. Patent Publication No. US 2013/0202656 on Aug. 8,2013, and entitled “Systems and Kits for the Fabrication of TissuePatches”; U.S. patent application Ser. No. 13/644,889 filed Oct. 4,2012, published as U.S. Patent Publication No. US 2013/0202674 on Aug.8, 2013, and entitled “Tissue Patch”; and U.S. patent application Ser.No. 13/644,907 filed Oct. 4, 2012, published as U.S. Patent PublicationNo. US 2013/0202675 on Aug. 8, 2013, and entitled “Systems and Methodsfor the Fabrication of Tissue Patches.”

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, “alkyl” refers to a straight-chain or branched saturatedhydrocarbon group having from 1 to 50 carbon atoms (“C₁₋₅₀ alkyl”). Insome embodiments, an alkyl group has 1 to 40 carbon atoms (“C₁₋₄₀alkyl”). In some embodiments, an alkyl group has 1 to 30 carbon atoms(“C₁₋₃₀ alkyl”). In some embodiments, an alkyl group has 1 to 20 carbonatoms (“C₁₋₂₀ alkyl”). In some embodiments, an alkyl group has 1 to 10carbon atoms (“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1to 9 carbon atoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl grouphas 1 to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkylgroup has 1 to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, analkyl group has 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments,an alkyl group has 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In someembodiments, an alkyl group has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). Insome embodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”).In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms(“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl(C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄),sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3-pentanyl (C₅), amyl(C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅), tertiary amyl (C₅), andn-hexyl (C₆). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈) and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents. Incertain embodiments, the alkyl group is an unsubstituted C₁₋₅₀ alkyl(e.g., —CH₃). In certain embodiments, the alkyl group is a substitutedC₁₋₅₀ alkyl.

As understood from the above, alkyl groups, as defined herein, are, incertain embodiments, optionally substituted. Optionally substitutedrefers to a group which may be substituted or unsubstituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” heteroalkyl, “substituted” or “unsubstituted”heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl,“substituted” or “unsubstituted” carbocyclyl, “substituted” or“unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or“substituted” or “unsubstituted” heteroaryl group). In general, the term“substituted” means that at least one hydrogen present on a group isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. For purposes of this invention, heteroatomssuch as nitrogen may have hydrogen substituents and/or any suitablesubstituent as described herein which satisfy the valencies of theheteroatoms and results in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(aa))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl,C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR′, —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(CC) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(CC) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR′, —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR′)R^(ff), —SH, —SR′, —SSR^(ee), —C(═O)R^(ee),—CO₂H, —CO₂R′, —OC(═O)R^(ee), —OCO₂R^(ee), —C(═O)N(R^(ff))₂,—OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee), —NR^(ff)CO₂R^(ee),—NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee), —OC(═NR^(ff))R′,—OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂, —OC(═NR^(ff))N(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)₂R^(ee), —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

-   -   each instance of R^(ee) is, independently, selected from C₁₋₆        alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆        alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,        C₆₋₁₀ aryl, 3-10 membered heterocyclyl, and 3-10 membered        heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,        heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl,        and heteroaryl is independently substituted with 0, 1, 2, 3, 4,        or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂ (C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

In certain embodiments, a carbon atom substituent is selected from thegroup consisting of halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR′,—N(R^(bb))₂, —SH, —SR^(aa), —C(═O)R^(aa), —CO₂H, —CHO, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa),—S(═O)R^(aa), —Si(R^(aa))₃, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl,heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl,C₆₋₁₄ aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups.

EXAMPLES

The following examples are intended to illustrate certain embodiments ofthe present invention, but do not exemplify the full scope of theinvention.

Example 1

This example describes formation of adhesive films containing variouspolyacrylic acids using a two-step non-aqueous dispersion anddisplacement method, and the determination of the burst strength of theresulting adhesive films. The adhesive films formed using the two-stepnon-aqueous dispersion and displacement method had relatively high burststrengths.

Adhesive films were made from 13 different polyacrylic acids. Theproduct number and molecular weight of each of the polyacrylic acids canbe found in Table 1. The polyacrylic acids differed in viscosity averagemolecular weight. The Carbopol products were cross-linked.

TABLE 1 Various Polyacrylic acids Product Molecular Weight Sigma 181285450,000 Sigma 306215 1,250,000 Sigma306223 3,000,000 Sigma 3,000,000Carbopol 971P NF >1,000,000,000 Carbopol 980 >1,000,000,000 Carbopol 981NF >1,000,000,000 Carbopol 5984 EP >1,000,000,000 Carbopol 71GNF >1,000,000,000 Carbopol PEMULEN 9TM TR-1 >1,000,000,000 CarbopolPEMULEN ™ TR-2 >1,000,000,000 Carbopol Noveon AA-1 >1,000,000,000Carbopol 974 >1,000,000,000

All films were made using a two-step non-aqueous dispersion anddisplacement method. Ethyl acetate was used as a dispersant and ethanolwas used as the displacement solvent. Briefly, films were made by adding1.66 grams of the polyacrylic acid powder to 12 mL of ethyl acetate. Thepolyacrylic acid/ethyl acetate mixture was then spread out as a 4 inch×4inch sheet, and after 12 minutes the dispersed film was exposed to amist spray of 200 proof ethanol. The film was then dried for 72 hoursand evaluated for burst pressure testing as described above. All filmscontained 99% of a single polyacrylic acid, except the Nov/Carb filmwhich contained a 50/50 (w/w) mixture of Noveon and Carbopol 974.

FIG. 2 shows the burst pressure for the adhesive films made with variouspolyacrylic acids. All polyacrylic acid polymer films had a burstpressure greater than 150 mmHg gauge.

Comparative Example 1

This example provides a comparison between adhesive films made usingdifferent methods of formation. Adhesive films were made using thetwo-step non-aqueous dispersion and displacement method described inExample 1 and via a one-step method, which utilized water. The filmsformed via the method utilizing water had a lower burst pressurecompared to the films formed using the two-step non-aqueous dispersionand displacement method described in Example 1.

The films formed via the method utilizing water were formed from 50/50(w/w) mixture of Noveon and Carbopol 974, TR-1NF, Sigma MW 1,250,000,and 71G-NF by adding 0.2 grams of each polymer powder to 1.5 mL of waterindividually. The powder and water mixture was applied over a 3.0 mmbiopsy punch hole as described in ASTM F2392-04. After 5 minutes ofincubation the burst pressure test was initiated and burst pressure wasrecorded in mmHg.

The films made using the two-step non-aqueous dispersion anddisplacement method described in Example 1, were made by adding 1.66grams of 50/50 (w/w) mixture of Noveon and Carbopol 974 to 12 mL ofethyl acetate, the polyacrylic acid/ethyl acetate mixture was thenspread out as a 4 inch×4 inch sheet, and after 12 minutes the dispersedfilm was exposed to a mist spray of 200 proof ethanol. The film was thendried for 72 hours prior to testing.

FIG. 3A shows the burst pressure for the adhesive films made from 50/50(w/w) mixture of Noveon and Carbopol 974 via the method involving water(referred to as water cast”) and the two-step non-aqueous method(referred to as “solvent dispersion). FIG. 3B shows the burst pressurefor the adhesive films made from various polyacrylic acids via themethod involving water (referred to as water cast”) and the two-stepnon-aqueous method (referred to as “solvent dispersion). Films formedvia aqueous methods had a significantly lower burst pressure (i.e., lessthan 50 mmHg (gauge)) than films formed from the methods, describedherein.

Comparative Example 2

This example compares the lap shear strength of adhesive compositionsformed from powder alone, a single organic solvent method, and thetwo-step non-aqueous dispersion and displacement method described inExample 1. The films formed as described in Example 1 had the highestlap shear strength.

Three different polyacrylic acid (PAA) films were formed to evaluate theinfluence of the formation method on lap shear strength. The differentcompositions were: i) a blend of 50% Carbopol 974P NF and 50% NoveonAA-1; ii) Carbopol 971P NF; and Polyacrylic acid average MW 1,250,000.

According to the powder method, 0.2 g of each powder was evenlydistributed onto the bottom of a 2×2.5 cm section of a glass microscopeslide (Gold Seal, Portsmouth, N.H., Cat#: 3049). A spray bottle withwater was then used to spray a second glass microscope slide and the twomicroscope slides were adhered together over the 2×2.5 cm overlap usingmoderate pressure. The two microscope slides were then incubated at 37°C. for 5 minutes.

The single non-aqueous polar solvent method was an ethanol solventcasting method. Briefly, 0.2 g of each PAA adhesive powder was mixedwith 0.35 mL of 200 proof ethanol to form a heavy paste. The PAA/ethanolpaste was then spread evenly over the bottom 2×2.5 cm section of a glassmicroscope slide (Gold Seal, Portsmouth, N.H., Cat#: 3049). The slidewas then allowed to dry for 24 hours at room temperature. After drying,a spray bottle with water was used to spray a second glass microscopeslide and the two microscope slides were adhered together over the 2×2.5cm overlap using moderate pressure. The two microscope slides were thenincubated at 37° C. for 5 minutes.

The two-step non-aqueous dispersion and displacement method described inExample 1 included mixing 0.1 g of each PAA adhesive powder with 0.75 mLof ethyl acetate (Sigma Aldrich, Cat#270989) to make a mixture. ThePAA/ethyl acetate mixture was then poured evenly over the bottom 2×2.5cm section of a glass microscope slide (Gold Seal, Portsmouth, N.H.,Cat#: 3049). The slide was then allowed to dry for 12 minutes at roomtemperature after which the coated slide was sprayed with a mixture of99% ethanol and 1% glycerin and then allowed to dry at room temperaturefor 24 hours. After drying, a spray bottle with water was used to spraya second glass microscope slide and the two microscope slides wereadhered together over the 2×2.5 cm overlap using moderate pressure. Thetwo microscope slides were then incubated at 37° C. for 5 minutes.

Adhesive strength via lap shear testing was analyzed using a TestResources Model 100Q225-6 Universal Test Machine with a 10 lb load cellas described above. In short, the two adhered microscope slides werelocked into position on the test machine using manual screw type grips.The two microscope slides were then pulled apart at a rate of 150 mm/minand data was recorded using the accompanying XY software.

FIG. 4 shows the lap shear data for the adhesive films. Films formed viathe powder and ethanol casting methods had a significantly lower lapshear strength than films formed using the two-step non-aqueousdispersion and displacement method.

Example 2

This example describes the effect of total polyacrylic acid weightpercentage on the adhesive and mechanical properties of an adhesivematrix. Adhesive matrices containing 25 wt. % filler and 75 wt. % of a50:50 (w/w) Carbopol 974P NF and Noveon AA-1 blend had a lower burststrength than films containing about 99 wt. % of the 50:50 (w/w)Carbopol 974P NF and Noveon AA-1 blend.

All films were formed by the two-step non-aqueous dispersion anddisplacement method described in Comparative Example 2, except differentcomponents were used to make the films.

The films including filler contained 75 wt. % of a blend of a 50:50, byweight, blend of Carbopol 974P NF and Noveon AA-1, mixed with 25 wt. %binder. Various binders that were tested included Karaya gum (1),Gelatin from porcine skin (2), Carboxymethylcellulose (3), Gum Arabic(4), Sodium Alginate (5), or Polyvinylpyrrolidone (6).

The films without fillers contained 99 wt. % of the 50:50, by weight,blend of Carbopol 974P NF and Noveon AA-1 (7).

FIG. 5 shows the lap shear data for the adhesive films. Films formedwith filler had a significantly lower lap shear strength than filmsformed from the two-step non-aqueous dispersion and displacement method.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” and the like are to be understoodto be open-ended, i.e., to mean including but not limited to. Only thetransitional phrases “consisting of” and “consisting essentially of”shall be closed or semi-closed transitional phrases, respectively.

What is claimed is:
 1. A method of forming an adhesive matrix,comprising: establishing a mixture comprising a non-aqueous liquid, afirst polyacrylic acid crosslinked with pentaerythritol and/or allylsucrose, and a second polyacrylic acid crosslinked with divinyl glycolon a substrate, wherein the amount of water in the mixture is less thanor equal to about 2 wt. %; applying a non-aqueous polar solvent to themixture on the substrate, wherein the non-aqueous polar solvent containsat least one of methanol, ethanol, propanol, and butanol; and allowingat least a portion of the non-aqueous liquid and the non-aqueous polarsolvent to evaporate to produce the adhesive matrix, wherein, after theevaporation, the sum of the amount of the non-aqueous liquid and thenon-aqueous polar solvent in the adhesive matrix is between about 0.001wt % and about 3 wt %.
 2. The method of claim 1, wherein the non-aqueousliquid is selected from the group consisting of ethyl acetate,tetrahydrofuran, diethyl ether, dioxane, pyridine, triethylamine,benzene, p-cresol, toluene, xylene, glycol, petroleum ether, hexane,cyclohexane, pentane, methylene chloride, chloroform, carbontetrachloride, dimethyl sulfoxide, dimethylformamide,hexamethyl-phosphoric triamide, picoline, and mixtures thereof.
 3. Themethod of claim 1, wherein the adhesive matrix is non-covalentlycross-linked.
 4. The method of claim 1, wherein the adhesive matrix isself-supporting.
 5. The method of claim 1, wherein the first polyacrylicacid and the second polyacrylic acid are hydrogen bonded to one anotherin the adhesive matrix.
 6. The method of claim 1, wherein the mixturefurther comprises a polyol or a non-ionic surfactant.
 7. The method ofclaim 1, wherein the amount of the non-aqueous polar solvant in theadhesive matrix is between about 0.001 wt. % and 1 wt. %.
 8. The methodof claim 1, wherein the mixture contains less than or equal to about 0.1wt. % water.
 9. The method of claim 1, wherein the weight percentage ofpolyacrylic acid in the adhesive matrix is greater than or equal toabout 90 wt. %.
 10. The method of claim 1, wherein the substratecomprises small intestinal submucosa and/or fibrin.
 11. The method ofclaim 1, wherein the adhesive matrix is a water-activated adhesivematrix.
 12. The method of claim 1, wherein the establishing stepcomprises applying the mixture to the substrate.
 13. A tissue adhesivecomposite, comprising: a tissue adhesive film positioned on at least aportion of a substrate, wherein the tissue adhesive film comprises: afirst polyacrylic acid crosslinked with pentaerythritol and/or allylsucrose; a second polyacrylic acid crosslinked with divinyl glycol; anda liquid comprising at least one of methanol, ethanol, propanol andbutanol; wherein: greater than or equal to about 90 wt % of the tissueadhesive film is made up of polyacrylic acid, and less than about 8 wt %of the tissue adhesive film is made up of the liquid.
 14. The tissueadhesive composite of claim 13, wherein the tissue adhesive film has aburst strength of at least about 100 mmHg gauge.
 15. The tissue adhesivecomposite of claim 13, wherein the tissue adhesive film has a lap shearadhesive strength of at least about 1.5 pound force.
 16. The tissueadhesive composite of claim 13, wherein the thickness of the tissueadhesive film does not vary by more than about 10% across its surface.17. The tissue adhesive composite of claim 13, wherein an amount ofwater within the tissue adhesive film is less than or equal to about 0.1wt. %.
 18. The tissue adhesive composite of claim 13, wherein thesubstrate comprises a material selected from the group consisting ofsmall intestinal submucosa, a fibrin-based substrate, diaphragm, porcineskin, bovine skin, human skin, pericardium, extracellular matrixcollagen, and amnion.
 19. The tissue adhesive composite of claim 13,wherein the weight percentage of polyacrylic acid in the tissue adhesivefilm is greater than or equal to about 95 wt %.
 20. The tissue adhesivecomposite of claim 13, wherein the tissue adhesive film is aself-supporting layer.
 21. The tissue adhesive composite of claim 13,wherein the first polyacrylic acid and the second polyacrylic acid arehydrogen bonded to one another in the tissue adhesive film.
 22. Thetissue adhesive composite of claim 13, wherein the liquid comprisesethanol.
 23. The method of claim 1, wherein the non-aqueous polarsolvent is made up of at least about 90 wt. % ethanol.